Clinical Pharmacokinetics

Fourth Level Pharm D Program

Second Semester 2024-2025

By:
Clinical Pharmacy Department Staff
Department of Clinical Pharmacy
College of Pharmacy
KFS University
Contents:

1) Introduction to Clinical pharmacokinetics

2) Concepts of Basic pharmacokinetics
3) Aminoglycoside TDM
4)Phenytoin TDM
5) Dose adjustment in renal failure
6)Vancomycin TDM
7) Bioavailability and bioequivalence
8) Digoxin TDM
9) Lithium TDM
10) Pharmacokinetics and pharmacogenetics
Chapter 1: Introduction to Clinical pharmacokinetics

Defmition of PK

•!• The science that study the rates of the transfer process associated with absorption,
distribution, metabolism, and excretion of drug through the body
•!• How the body affects the drug

Phannacodynamics

•!• Pharmacodynamics refers to the relationship between the drug at the site of action
(receptor) and pharmacologic response
•!• How the drug affect the body

Importance of Clinical PK

•!• TDM (therapeutic drug monitoring)

•!• Dose adjustment in special populations (ensuring the right dose)
•!• Diagnosis and evaluation of kidney diseases
•!• Bioavailability studies
•!• Evaluation of drug interactions

Why need TDM?

•!• Some drug have narrow therapeutic window (NTW)

•!• Individual variations "Patients usually do not response in a similar way when they are
placed on identical dosage regimen".
•!• Some may demonstrate adequate response, others may demonstrate toxicity, and other
may not be affected at all by the drug.
•!• So, make therapeutic drug monitoring to these drug for each patients

ADME

•!• Pharmacokinetics (PK) involve four main process(ADME): absorption, distribution,

metabolism, and excretion
•!• These events don't occur as single separated steps but all process are going at the same
time
•!• Each process has its own rate and its own kinetic parameters

Plasma concentration curve

•!• Therapeutic and toxic effects of drugs depend on drug concentration at receptor site
(impractical to be measured, so the solution is plasma concentration curve)
 ®
•!• Plasma concentration is the simplest widely used method to evaluate the therapeutic and
toxic effect ofthe drug
•!• Absorption increase plasma concentration while metabolism and excretion decrease
plasma concentration
•!• Distribution in most cases have no significant effect of plasma concentration (one
compartment model)

The changes in drug concentration are as following:

•!• A- An increase in the amount of drug in the body (absorption)

•!• B- A decrease in the amount of drug in the body (metabolism and excretion)
•!• C- No change in the amount of drugs in the body (distribution)

The change in blood amount after oral administration:

Some drugs are administered IV, so these agents have no absorptive phase associated with their
pharmacokinetic profile.

IV administration of drugs is followed by distribution and elimination, and thus the time-amount
profile ofthe drug in the body is a decreasing function as shown below.
The drug a moun t-time profile in th e body is a n
in c reasin g, a nd th e n decreasi n g f"un ctio n as sh own
below.

o; 300
-=
j
200

i
-<
0 3 6 9 12 15 18

Tim e (hi')

•!• Some drugs are administered IV, so these agents have no absorptive phase associated
with their pharmacokinetic profile.
•!• IV administration of drugs is followed by distribution and elimination, and thus the time-
amount profile of the drug in the body is a decreasing function as shown below.
 The tirne-arnount profile of the drug in the body is a
decreasing function
20

16

12

40

0 2 4 6 8 10 12
Time {hr)

iv
po

Routs of administration

Iv: no absorption occur

Other parental: IM, SC

Oral: sustained release(SR), sublingual

Transdermal: creams, ointments

Inhalation : aerosols and nebulization

Absorption & bioavailability

bioavailability means the percent of the drug dose which reach systemic circulation (as
indicated by plasma concentration)
It is considered 100% in case of IV administration
Bioavailability is changed by factors affecting drug absorption

First pass effects

The phenomena where the concentration of a drug is greatly reduced before it reaches the
circulatory system reducing drug bioavailability.
The gut and liver metabolizes many drugs to such an extent that only a small amount of
active drug reach the rest of the circulatory system from the liver.
Sublingual route shows no first pass effects
Drug

Enterohepatic circulation

This refers to the circulation of drugs from the liver to the bile, then to the small
intestine, followed by reabsorption again through the enterocyte (often by the bacterial
help) and transport back to circulation and liver.
Drugs may be toxic as they reach unexpectedly high concentrations.
Enterohepatic circulation increase plasma concentration of drugs like oral contraceptive,
estrogen
Secondary peak is found in plasma concentration curve
P glycoprotein

Also called multidrug resistance protein 1 (MDRl)

an important efflux protein of the cell membrane that pumps many foreign substances out
of cells.

Found in:

intestinal epithelium (decrease drug bioavailability)

proximal tubule of the kidney (remove drug in urine)
endothelial cells composing the blood-brain barrier (preventing entry to the brain)
Some cancer cells (preventing drug entry causing cancer multi-drug resistant).

P<>.rt:ed ._ein

• P-glycoprotein
•
Inhibitor

Distribution of drugs

After absorption to blood stream, drug is rapidly distributed into the interstitial and
intercellular fluids
Liver, kidney, brain, and other well-perfused organs receive most of the drugs
Plasma proteins bound to many drugs. This bounded drugs have no action at receptor site
and only unbounded fraction has a pharmacological action
Displacement of highly bounded drug from plasma protein by other drugs can affect the
pharmacological action greatly ex: warfarin
 Drug distribution determine the model of drug kinetics (one compartment or two
compartment)
®
- -
=J
=
--
.....-==
-
Metabolism

Metabolism of drug occur mainly in the liver

Metabolism involve two main process

1-phase 1 oxidation reaction

2-phase 2( conjugation) reaction

Excretion

Kidney is the main organ for excretion of drugs and their metabolites
elimination from lung is important mainly for the elimination of anesthetic drugs
Some drugs may be excreted in saliva and sweetings

Orders of reactions

Example of zero order reaction

A pharmacist weighs exactly 10 g of a drug and dissolves it in 100 mL of water. The solution is
kept at room temperature, in order to measure the stability and samples are removed periodically
and assayed for the drug. The pharmacist obtains the following data:

Drug Concentration (mg/mL) Time (hr)

100 0
95 2
90 4
85 6
80 8
75 10
70 12

Zero order equation

dA/dt =-ko
By integration

A= -k,t +A,

Where A o is the amount at time zero

"E 100 Intercept:= A0

b:o
..§.
._"g' 80
I!!

ie 60
0
Slope=- Ko
40

20

0
0 3 6 9 12 15
Ti me ( hr)

Example of first order reaction

A pharmacist dissolves exactly 10 g of a drug into 100 mL of water. samples are removed
periodically and assayed for the drug. The data:
Drug Cone (mg/mL) Time(hr) Log Cone 100.00 0 2.00
50.00 4 1.70
25.00 8 1.40
12.50 12 1.10
6.25 16 0.80

The plot o"f A versus tirne is not a straigh't line

20

16
bi 5
..<s

"S 12

e
""
<C
8

40

0 :z 6 8 10 1:Z
Time (h.-)

Equation for first order kinetics

 dA/dt=- K A

A= Ao e-kt

By integratio n
Ln A= -Kt+ In Ao

since ln= 2.303 log

Log A= -Kt/2.303 + log Ao

The plot of log A vs time is a straight line

3.0

2.5 LogAO

0.2

t>.O
Slope = -K/2.303
_, 1.
5

1.0

0.5

0.
0 0 2 4 6 8 10 12
Time (hr)

Compare between first and zero order kinetics by completing the following table

First Zero
Log A= -Kt/2.303 + log Ao
A=-kot+Ao
Nature of The rate Cone or amount Amount independant
change dependant

Half life equation t 1/2= 0.693/k t 1/2= 0.5 Ao/ko

Nature of Half life constant Not constant
Graph presentation Straight line on semilog Straight on rectangular
coordinate
Slope k/2.303 on semilog Ko
paper
intercept logAo Ao

K unit hr-1 Mg/hr

Graphs presentation on excel sheet

Express these data on both rectangular paper and logarithmic paper

 X

0
y

0.001
®
1 0.02
3 0.08
7 10
10 400

.., 10 +

•
""C
....
....
aJ
+
""C + +
c: 8
:::l
:I: +
+
.... +
+

y 6 +
+
+ ..
t
+

4 + .. +
t +
+

2 + .. +

+ .. +

0
0 5 X 10 15

10000

1000 t
+

y
100

10
• I
1 t t t
0.1
•
0.01 t

0.001
0 5 10 15

Phannacokinetic Models:

•!• A model is a hypothesis enables using mathematical terms to simulate the rate processes
of drug absorption, distribution, and elimination (metabolism and excretion)
 ®
•!• Compartment models are based on linear assumptions using linear differential equations
•!• It enables Predict plasma, tissue, and urine drug levels with any dosage regimen

One Compartment Model

Before Aftet'"
Administ ration Administrat ion

Two Companment t.Aodel

Immediately After
Administration
Before Administration After o istlibution
Equilibrium
 Model
I

One-compartment model

•!• In this case the plasma and all perfused organs deal as one unit (the central compartment)
•!• The drug is both added to and eliminated from a central compartment.

.rborp1"ion elimino=t t- ion

Oral d ose

eliminat ion

IV d ose

Two-compartment model

•!• In a two-compartment model, drug can move between the central ( plasma compartment and
highly perfused organ) to and from the tissue compartment(peripheral compartment).
•!• In this model, in most cases, there is no elimination from tissue compartment and the drug need to
be transported again to the plasma in order to be eliminated

absorpt ion
Penpheral
Central compartment
compartment
Oral dose

l
elimination

Central Peripheral
compartment compartment
IV dose

elimination

Pharmacokinetics- pharmacodynamics interface

Plasma concentration and pharmacologic response

!-Concentration response plot: increase concentration increase response till reaching maximal response (
Most drugs)
 Maxsmal
efficacy

Poten
Dose (log1o scaJe)

Hysteresis loops

The response not related to the dose, the cause may be:

a- counterclockwise hysteresis due to increased sensitivity or formation of active metabolite

b- clockwise Hysteresis due to tolerance or formation of inhibitory metabolite

020 70 120 170 220

Cocoine (ng/rnL)

Example

Three new drug for treating diabetes were introduced in the market. The following table represent the
relation between the plasma concentration and the drug effects as indicated by the decrease in blood
glucose level. For each drug determine the pharmacokinetic and pharmacodynamic interface after plotting
the concentration effect graph
 drug A drug B drug C

Effect Effect Effect

(BG decreas.,) ( BG decrea soe ) (BG decreasoe)

5 2 2 2

10 4 4 4

20 8 8 8

30 16 12 10

20 18 8 6

15 12 G 4

10 10 4 2

5 6 2 1

Antibiotic PK/PD interface

Time-dependent antibiotics Concentration-dependent antibiotics

c c
.Q Parameters of Interest .Q Parameters of Interest

c ·Time above MIC c ·C..., I MIC ratio

·AUC I MIC ratio
c c
0 0
(.) (.)

MIC MIC

nme nme

Penicillins, linezolide aminoglycosides,fluoroquinolones

MIC:Minimum inhibitory concentration

Chapter 2: Concepts of Basic Pharmacokinetics
•!• compartment model single IV dose
•!• compartment model single oral dose
•!• compartment model IV infusion
•!• multiple dose administration
•!• Two compartment model single IV dose

Single IV dose

Equation for single IV kinetics

A= Ao e-kt

sin ce ln= 2.303 log

Log A= -Kt/2.303 + log Ao

elimination

IV dose

Presentation of IV curve on semilog paper

Slope= K

Volume of distribution

Volume of distribution= Dose of drug/initial plasma cone

Vd=dose/Cpo

•!• Practically, we canot measure concentration at time zero

•!• We can determine it by drawing the data and extrapolating the curve to time zero
TYz for IV single dose

it s constant and does not affected by th e

concentration of the drug

t = ln2 0.693
k k

The btz can be estimated by observing how

long it takes for any cone on this line to
decrease to one-half of its value.

Clearance (CI)

Clearance (Clot TBC) is the volume of plasma that is completely cleared of the drug per unit time

Cl= K Vd

•!• The TBC is the product of the first-order rate constant (K) and the Vd, and has dimensions of
volume/time.
•!• Cl is constant for the same drug
•!• The total body clearance will be equal to the renal clearance + hepatic clearance + lung clearance.
•!• Cl= renal clearance+ liver clearance

AUC (the area under the curve)

The integral of plasma cone with respect to time after an IV dose is the area under the plasma cone-time
curve (AUC). Which has units of mass-time per volume (mg.hr/liter).

AUC = Dose !K Vd = CPo/K

TBC = Dose/ AUC

* Since the TBC of a drug in a given subject is constant, the AUC is proportional to the given dose.

Dose
AUC TBC

Cpo
AUC K
Single oral dose
Plasma concentration curve

c
---
---r-------
Th erap
· eutic
MTC

--- I:
.52
c
c
0
(.)

Dose= SOO mg

e
-= 400 Amount of drug I.n the GIT
s::
::::1
0

E Amount of drug I.n the body

::'t, 300
::::1
0

200

100

0
0 2 4

absorption elimination

Oral dose
Equation for single oral dose

FDKa
A ka -k

Turning into concentration

_ FDKa
con e Vd(ka-k)

ln ka -ln k
t max ka- k

F (bioavalability)

A[ / Coral
F = AUCiv

AUCiv .Dose
Cl

FDuse
A [ .7Coral = Cl

---------------------------------,

300

Post absorptivephasl:!

Absorption pha se

0------------------------------
0 6 9 12 15
nm e (hrl

Equation for single oral dose elimination part

after the end of absorption

FDKa
Ln c= In VdJw-k) kt
Continuous IV infusion

The main advantage for giving a drug by continuous IV infusion is that

(l)IV infusion allows precise control of plasma drug concentrations to fit the individual needs of the
patient and the duration of drug therapy may be maintained or terminated as needed using IV infusion

(2)For drugs with a narrow therapeutic window (eg, heparin), IV infusion maintains an effective constant
plasma drug concentration by eliminating wide fluctuations between the peak (maximum) and trough
(minimum) plasma drug concentration.

(3)the IV infusion of drugs, such as antibiotics, may be given with parenteral nutrition that include
electrolytes and nutrients.

(4) Reduce toxicity on body as incase of immune reaction and vein damage by push IV or intermittent IV
administration

Steady-state Wash-out

Cone

nme

Graph for IV infusion

 cone

Steady state

Time

The steady state principle is also known the plateau principle

Equation for IV infusion

Rate of input = rate of output

R=KAss

Ass= R/K

Cpss= Rl k Vd = R/Cl

Time Needed to Reach C SS

Mathematically, the time to reach true steady-state drug concentration, C SS, would take an infmite time.
The time required to reach the steady-state drug concentration in the plasma is dependent on the
elimination rate constant of the drug for a constant volume of distribution.

cone

Steady state

Time
sameTime
Loading Dose

The loading dose, DL, or initial bolus dose of a drug, is used to obtain desired concentrations (steady
state) as rapidly as possible.

DL= Cpo Vd Css= Rl k Vd

in order to instant reach steady state

Cpo = Css

so:
DL=CssVd or DL=R/K

Graph for sustained release tablets

cone

Steady state
--y----=<,
I I
I

T Time

•••• ••
-
DIAMICRON l.tfk 60 mg
,.«tfNd,....- Release
 Multiple-Dosage Regimens:
There are two main parameters that can be adjusted in developing a dosage regimen:

(1) the size ofthe drug dose

(2) the frequency of drug administration (ie, the time interval between doses).

Presentation of IV Multiple dose curve

- "' -- ------1----------------
"'J- \j \j \j _

30T-------------------------------------------------

6 12 18 24 30 36
Time (hr)

Equation for multiple IV dose

A max= D/ ( 1-e-kr) A
min =A max e -kr
Dose= Amax-Amin

Cp max= D/ Vd( 1-e-kr)

Cp min =Cp max e -kr
D!Vd = Cp max- Cp min
Presentation of Oral Multiple dose curve

1'\ -r, --- ---

r{\J ' '\J :0 _ \
--
0)

Equation for multiple oral dosage

Similar equation can be applied if (F) bioavailability coefficient was added

Cp max= FD/ Vd( 1-e-h)

F DN d = Cp max -Cp min

Presentation of IV Multiple dose curve

20

c:
0
· 15
E
c»
<.>
c:
0 10
<.>
Ill
E
1/)
Ill
a: 5

Time (h)

Dosing regimens

Before designing a dosing regimen, several points have to be considered:

•!• Is the drug has minimum effective concentration (I\.1EC) that have to be achieved in order to
produce the therapeutic response?
•!• Is the drug has a minimum toxic concentration has to be maintained below in order to avoid toxic
effects?
 ®
•!• Is the difference between the MEC and the MTC is large or small (therapeutic index)? (if small
therapeutic index exists, frequent administration of small doses will be necessary to avoid large
fluctuation in plasma concentration)
•!• Is there a compliance problem with the drug? So, reducing frequency may be recommended

Time to reach steady state

z
0

a:
w
, '--------......-----'
0
z Steady-State Concentrations
0 •Proportional to dose/dosage interval
0
•Proportional to F/CL
Fluctuations -------------------'
•Proportional to dose intervaVhalf-time
•Blunted by slow absorption
0------- ---- --- ---- --- ---
0 1 2 3 4 5 6
TIME (multiples of elimination half-time)

Loading dose

If need to rapidly reach the desired concentration, Loading dose may be used

LD = Cp. Vd

Cp is the average concentration at steady state

Average concentration at steady state

The average concentration is not the mean value of the maximum and the minimum plasma concentration

Wagner equation (rate in =rate out(FD/t=TBC Cpss)

Cp Avg= FD/K Vd r

AUC=FD/KVd

Cp Avg=AUC/r
Presentation of IV Multiple dose curve

25

:._J, ' 20
Cl
sc:
.2 15
1§
E
Cl)
(.)
c:
0
(.)
10

E
"'
.!!!
(l. 5

8 16 24 32 56 64 72 88 96
Time(h)

Effect of dose change on PK parameters

concentration Constant parameters

Single IV Increase Cpo Increased K,Vd, T112,TBC
Linear linear
Single oral Increased Cmax Increased K, Ka, Vd, T112, TBC
linear relation linear

Continuous Increased Css K, Vd, T112, TBC

infusion Linear relation

Multiple Increased cmax and K, T, ka, Vd, T/l2, TBC

dose emin in linear relation
Two compartments model

dist ribution

K21
Central Peripheral

compartment compartment
K12

elimina tion
1
IV dose tvvo compa rtment

1ooor--------------------------------------------------------------,

:::1 A ---."1.1 -Pt

"liD e
.§.
c
0

-
+=
c
.....
(I

c
8
(U

.,
E
(U
a:
10
0 2 6 8 10
Time (hr)

Equation for two compartment model depending on graph presentation

-at
Cp==Ae
A the intercept for the distribution phase
B the intercept for the elimination phase
a the slope of the distribution phase
B the slope of the elimination phase
Hybrid first-order rate constants

K K
10 21
ap
K + K + K =(a+ P)
21 10 12
 Chapter 3: Aminoglycosides TDM

Introduction

It is an IV infusion over a short period of time.

Advantages of intermittent IV infusion:

1. The risk of incompatibility is reduced.

2. Suitable for some drugs like aminoglycoside to avoid drug toxicity.

3. The risk of fluid overload is decreased.

concentration
time

Following repeated administration of these short IV infusion, the drug will accumulate in the body until
steady state is achieved.

At steady state, the maximum and minimum plasma concentration will be constant if the dose, infusion
duration, dosing interval are kept constant.

10

Time (h)

Ko = infusion rate= dose/t' (mg/hr.)

At steady state
Repeated administration of intermittent IV infusion will lead to the accumulation in body until reaching
steady state. At steady state, we will have Cssmax (peak) after the end of infusion at time t ', and
Cssmin(trough) just before the drug infusion.

10

Cssmi n=trough

Time (h)

• The pla sma conc entration at trough (Cssmin)

CP, -m in - cpss7nuxe - k('-r - t' )

The plasma concentration at peak (Cssmax)

-
CP ssmax - KVd
(1- -e
-kt' ) c
+ · P mine -kt'

By substitution for by combining the two equation

together, the following equation will be obtaine d
C k (1-e-k )
p ssma>< kVd(1- e -k"')

Loading dose

The concentration at steady state depend only on the administration rate (infusion dose, t', -r-)
assuming the TBC is constant in this patient.
Similarly, it will take 5-6 half life to achieve the steady state.
Administration of loading dose can lead to immediate reaching the steady state without affecting
the concentration at steady state. As the nature of AG is concentration dependent. Cmax is used
for Loading dose calculation

Loading Dose:

LD = Cssrnax x Vd

Cone depend. Vs time depend.

 c
0 .--PuillllC (Conctntration-Deptndent)
D
r
t
D
t
Timt (Tcimt-Dtptndent)
..
>n

3
I
. - . -.-.- . -. --!ll C
0
D
0
.
Time (Hou rs)

At steady state

Increasing the infusion dose, will result in proportional increase in Cmax and Cmin at steady
state.
Increasing the infusion time of the same infusion dose will result in decreasing the Cmax and
slight higher Cmin at steady state as larger amount of the drug is eliminated during the longer
infusion time.
Increasing the interval time (same dose and infusion time), will result in lower Cmax and Cmin at
steady sate.

g n1::amic:in 120 mg giv-e.

"10

J
a
...=.
g nt::amicin 120
-=
c:::::

-ce:
6

4
mg gi-v

Bc:::::
8
2 -----·--
<>
10

Aminoglycoside pharmacokinetic

In practice, the traditional infusion time for aminoglycoside (AG) 1s 0.5 or 1 hour.

gentamicin 120 mg given as a Y. hour infusion

10

gentamicin120 mg given as a 1-hour infusion

ol--- -- ==
0 2 4 6 8 10 12
Time (h)

Conc.-dependent bactericidal effect (Cmax value is most important than time above MIC)

Nephrotoxicity and Ototoxicity are associated with high trough concentrations.

ADMEforAG

Bactericidal: Aerobic gram -ve and some aerobic gram +ve

Oral bioavailability (F):

Not absorbed (poor bioavailability), may be given orally for local effect on GIT (neomycin,
streptomycin).
IM bioavailability: Almost 100% except in obese patients
Plasma protein binding is< 10% (insignificant)
Almost completely eliminated unchanged by the kidney
Removed by hemodialysis.
Contraindicated if CrCl< 20ml/min or rapidly changing renal function

PHARMACOKINETICS: Distribution

• Volurne of distribution (Vd)0.26 (0.2-0.3) L/kg

Age Estimate d Vd
Full-term neonat es (Gestational age- 40 vvks) 0.4-0.5 L/kg
Infants ( 6 months-2 years ) 0.3-0.4 L/kg
Children ( > 2 years) 0.26 L/kg
A scites,burn,cystic fibros is 0.35-0.4 L/kg
dehydration 0.2-0.25 L/kg

ABW/IBW Suggested Weight

0.9- < 1 . 3 ABW
1.3 Adj BW **
0. 75- < 0.9 IBW*
<0.75 1.13 ABW

**AdjBIN = /BIN + 0.4{ABW - IBIN}

Half life and elimination rate constant of population

• Almost completely eliminated unchanged by the kidney

• Use ABW if lower than IBW
K = 0.00293 (Cicr) + 0.014

Creatinine clearance (mUmin)

T1/2 in adult = 2hr in adult

AG DOSING: Conventional Dosing
 Indication Goal Peak level* Goal Trough level** (mg/L)
Gent/Tobra Amikacin Gent/Tobra Amikacin
UTI,Endocarditis 3-5 12-15 < 2 (0.5-1) < 5 (1-4)
(synergy)
Bacteremia 5-7 20-25 < 2(0.5-1) < 5 (1-4)
(septic shock risk)
Pneumonia (CAP) 8-12 28-30 < 2(0.5-1) < 5 (1-4)

Extended interval aminoglycoside dosing regimen:

*Gentamicin I tobramycin: 4-7 mg/kg/24 hr, Amikacin: ll-20 mg/kg/24hr.

AG Peak level(mg/L) Trough level (mg/L)

Gentamicin/ 20-30 <1

Tobramycin
Amikacin 55-60 <4

2
0
0
-r
.. ... -r,-

Despite the extremely high peak concentrations obtained during extended-interval dosing of
aminoglycosides, increased nephro/ oto-toxicity is not seen in these patients.

Monitoring AG toxicity

Symptoms for ototoxicity:

-Dizziness, tinnitus, deafness.

-First signs may be loss of high-frequency hearing -may be the spouse or caregiver noticing that
the patient cannot hear certain pitch sounds.
-Deafness is irreversible and may occur after therapy has been stopped.

Symptoms for nephrotoxicity

-serum creatinine increases of0.5-2 mg/dl.

-Usually reversible
Monitor [Cr] at least weekly in hemodynamically stable patients and More frequent monitoring
(daily) in high risk patients (old age, high trough concentration).
Approaches for Aminoglycoside dosing

A- initiation of AG dosing "Empiric"

To Initiate an appropriate dose

Determine loading dose (if needed)

Determine maintenance dose
Monitor the patient for patient peak and trough value

Steps:

1-estimate K and vd for population

2-decide peak and trough value
3-calculate -r= dosing interval (hr.)
Ko= infusion rate = dose/t' (mglhr.)

Case study 1 in TDM

0Patient: JM
0 Age: 50 Gentamicin Dose Per Pharmacy
0Height: 5 ft I 0 in
OWeight: 70 Kg
O Gender: M
O[Cr]: 0.9 mg/dl (stable for 5 days)
Olndication: gram-negative Pneumonia.

Gram-negative pneumonia patients treated with aminoglycoside

(peak value 8-12 IJ.g/mL; trough <2 IJ.g/mL to avoid toxicity).

Recommend a gentamicin dosing regimen for this patient using

conventional dosing.
Case l:Answer

1. Calculate IBW? IBVV = 73 Kg

2. Estimate creatinine clearance:

CrCI= 97 mllmin

2. Est in1ate elin1in at ion 1·ate co n stant (ke) an d h alf-life (t 112).

Ike= 0.00293(CrCI) + 0.014 = 0.00293(97 mU min)+ 0.014 = 0.298 h
L t 1,2 = o.693tkl! = o.693to.29s h- = 2.3 h
1

3. Estilnate volume of distribution (V): The patient does not have

any condition that tnay alter the normal Vd value (0.26 L/kg)

Vd- 0.26 x ABW (70)

Vd=18. 2 L

4. Choose desired steady-state serum concentrations.

Set Cssmax = 9 J.lg/mL and Cssmin = 1 J.lg/ mL
5. Use intermittent intravenous infus i on eq uations to compute dosing
intervaL
T= 8.4 hr= 8 hr
In t his case, the dosage interval would be rou nded to 8 hours.
6. Use intermittent intravenous infus ion eq uations to compute dose(l
hr. infusion using 't of 8hr).
Ko= 172 mg/1 hr::::: 170 mg
7. The prescribed maintenance dose would be: 170 mg over 1 hr.
every 8 hours.
NB: even if th e infusion time is 30 min, th e same dose will be
given as no significant c hange in practical effects

Case 2: extended interval

CIPatient: J M
CIAge: 20
CIHeigh't: 6 ft 3in [i obran ci'n Dose Per Pizarinacy
CIWeigh't: 76 Kg
CIGender: M
Cl[Cr]: 1.1mg/dl (stable for 5 days)
Cllndication: gram-negative Pneumonia.

Recommend a tobramycin dosing regimen for this patient

using extended dosing interval.
(Note:Set peak= 30J
g, / mL and trough = 0.1J
g, /mL)
Case 2: answer

Dos ing weight ?IBW= 50 + 2.3(Ht - 60) = 50 + 2.3(75 - 60) = 85 kg

Est in1ate creatinine cl earance:

rC = [( 140 - age)BW)/(72 • SJ = [(140 - 20 y)76 kg)/(72 • 1.1 mg/ L
CrCI = 115 mUm in
Estin1ate elitnination rate constant (ke) an d half-life (t 112).
• = 0.00293(CrCI) + 0.014 = 0.00293(115 m Umin) + 0.014 = 0.351 h-1
t 111= 0.693/k.= 0.693/0.351 h-'=2.0 h

Est inmt e volume of distribution (V).

0.26 Ukg (76 kg)= 19.8

Ch oose desired steady-state serum concentrations.

We need steady-state peak of more than 20 J..Lg/mL; steady-state trough
should be less than 1 J..Lg/mL to avoid toxicity.
Set Peak = 30 f.l.g/mL and trough= 0.1 f.l.g/mL.
Use intermittent intravenous infusion equations to compute dosing
interval.
't = [(In Css,....."- In Css""")lk.,J + t'= [(I n 30tg/mL - I n 0.1g/mL)/0.35 1 h1) + 1 h = 17.3 h
In this case, the dosage interval would be round ed to 24 hours
(more clinically acceptable).
ko = Css""'"k<'V[(1 - e k.-<)/(1 - e .....')]
[ko = (30 mg/L - 0.351 h ' - 19.8 L){[1 - e o 31 h '4 h':J/[1 - e .o31 h ' w • h)]}= 704 mg

Use intermittent intraveno us infusion equation s to compute dose (1 hr.

infusion).
The prescribed maintenance dose would be:700 mg every 24
hours.

extended interval aminoglycoside dosing regimen using Hartford nomogram:

*extended interval also include 36 hr and 48 hr depending on Crcl. The recommended interval can be
calculated by Hartford nonogram using 7 mg/kg dose
 "1 4
=r
"1 2
.a,
"10
V>
Dose every
<0 24 hours
Ci..

.s a
,§
<0 6
.l:::o
liS
<..>
c: 4
8
2
6 7 a 9 "10 "I "I "1 2 "13 "1 4

Hours since admi nistration

Fig. 6.16 Dosing of amlnoglycosides using the Hartford
nomogram. The nomogram Is used to determine the dose Interval for 7 mg
doses of gentamicin or tobramycin, using measurements or drug levels in
plasma
6-14 hours after a single dose.

NB: time calculated from the Start of infusion

Example "apply on clincalc"

Using Hartford nomogram recommend the dosing interval for extended interval gentamycin if the patient
weight 70 kg height 70 inches, the sample taken after 10 hours gentamycin concentration is 7 mg/1

c-Aminoglycosides PK Monitoring at steady state

The most common is to monitor at steady state.

Peak: drawn Yz hr. after a Yz hr. infusion or at the end of al hr. infusion.
''tissues are not in equilibrium yet allow Yz-hr waiting period before peak is measured"
Trough: drawn just before the next dose.
Determine Patient-specific parameters (k and Vd) and adjust if needed then

10
< I
- -k(t-t')
Cpss,min -Cpss,max e

t roug h Ko (1- e- kt')

sample Cpss, max
kVd(l- e- kt)
Time (h)

Dose adjustment at steady state

1-measure: At steady state, take two samples (for peak and trough) and measure AG
concentrations.
2-determine: using the measured peak and trough value, determine K and Vd for this
patient
 • 3- decide: decide the required peak and trough
• 4-claculate the required Ko, T for this patient: adjust the dose if required based on
patient specific parameters

In TDM, monitor for AG cone. occur every 1-3 days until stabilization then every week.

• Monitoring is not require ifthe expected length oftherapy <3 days (e.g. UTI)

Example: In referring to case 1,

• Later on, the pharmacist measured two plasma concentration at steady state for
gentamycin, the patient peak concentration and trough concentration were 9.5 mg/L
and 2.2 mg/L. Based on patient PK parameter,calculate the required dosing rate and
interval.

Apply on clincalc.

B- After receiving the first dose

• After the end of infusion of the first dose according to population parameters, Three
sample of AG is obtained in the period after the end of drug infusion and analyzed for
AG concentration
• These concentrations are presented graphically, from the obtained straight line
determine the K (elimination rate constant) from slope ofthe curve and Tl/2
graphically.
• Then by extrapolation ofthe straight line determine the concentration at the end of
infusion of the first dose (Point A)

B-AG Dosing after receiving the first dose

t:he:n from the follovvi:ng equat:io:n det:errrrine the "Vd for this
patient:
Cp = Ko (1- -kt:')
KVd e

By using patrnet :K and Vd, determine the admin.istration

rate(:Ko, t:', T) required to get: the desired Cmax a:nd Cmin.

-
Concent:ra t:l on

-
A

.> time
 Chapter 4: Phenytoin TDM
Concepts for non-linear kinetics

•!• Some drugs do not follow first order kinetics specially in elimination process . So, these
drug will have elimination that changes as the concentration change.
•!• In this case, the steady state concentration will not be proportional to the rate of dosing.
•!• This is called nonlinear kinetics or capacity limited kinetics or kinetics of saturation

Clinical Example

•!• After 2 weeks on 300 mg/day of phenytoin, the measured cone. of phenytoin is 6 mg/L.
(Target therapeutic range is 10-20 mg/L)
•!• The physician doubled the dose rate to 600 mg/day to double the concentration achieved.
•!• 2 weeks later the patient calls the pharmacy with complaints of double-vision and
difficulty walking. A concentration is drawn = 36 mg/L(Explain the case ?)

Linear vs non-linear kinetics

•!• Linearity: the direct relation of elimination to the concentration of the drug in plasma.
The dose change result in propotional change in cone and AUC
•!• Non-linearity: there no direct relation between drug concentration and the elimination of
drugs. The dose change result in non-propotional change in cone and AUC
•!• Common examples ofthese drug: valproic acid, phenytoin
•!• Non-liner pharmacokinetics can occur in any ADME process but capacity limited
elimination (most common)

After IV bolus dose administration (on semilog paper)

•!• Bin case oflow drug concentration (both linear and non-linear)
•!• A in case of large drug concentration in non Linear
•!• C in case of large drug concentration in linear pkarmacokinetics

Michaelis- Menten enzyme kinetics

•!• Michaelis- Menten enzyme kinetics expresses the non linear kinetic of some drugs.
•!• Enzyme (E) react with substrate(S) to form enzyme-substrate complex (ES) then the
product (P) is formed and the enzyme go back to react again with another substrate.
 Ks kc..l
E + S ES----+ E + P

• Thus, the qua ntitative relation between the rate of

kinetic proc ess and plasma concent ration ca n be
expressed as

V= VmaxS
Km + S

• Km (michaelis menten constant) depends on K1, k2, k3

• Vmax (maximum reaction rate) depends on total
enzyme amount

Graphical presentation
0.3G

0.30 vmax
-

0.20
.$
0.20
0
:u
ro 0.15
Q)
a:::
0.10

Km
0.05

0.00
!/
0 1000 2000 3000 4000

Concentration of substrate

After IV bolus dose administration

When Km>>>>Cp at low drug concentration

•!• V= (Vmax/km) x Cp
•!• The reaction appear similar to first order kinetics

When Cp>>>>Km at middle drug concentration

•!• V= (Vmax/Cp) x Cp= Vmax

•!• The reaction appear similar to zero order kinetics

When Km=Cp, the V/Vmax=

•!• This means that Km is the constant which equal the substrate or plasma concentration at
which the process rate is half maximal
Compare linear and capacity limited kinetic After IV bolus dose

K Vmax
Central Central
compartment compartment Km

-dA/dt= K A9KVdiCp -dA l vmaxiCp

dt I Km + Cp l
No stra ight line simple equation

linear capacity limited

Comparison at steady state of multiple ornl administration

For linear kinetics

•!• At steady state of IV infusion rate in = rate out

•!• R=KVd x Cpss

At steady state of multiple administration

•!• rate in = rate out

•!• FD/'(= KVd x Cpss
•!• KVd= TBC

For non-linear kinetics

At steady state of IV infusion rate in rate out

Vtnax C
R = pss
Km + CPss
At steady state of multiple administration
rate in = rate out
FD/T= _Vm_ax Cpss
Km+CPss
Vmax
TBC= Km + CPss
Half life and clearance for non-linear kinetics
TBC= v_ , _a.,.x
Krn+lP.s.s

T 1 2= 0.693Vd/TBC

0.693Vd
T1 r ?- (krn + Cps s )
V tnax

From t his t\N o equation, \Ne conclude that the T1/2

and TBC is not constant: but depend on the CPss

Steady state of multiple oral administration of linear kinetics

• From the equation FD/T= v max Cpss
K1nTCP.s:s

• VV e ca n conclude that in order to determine

the dosing inte rva l to reach speci fic steady
state concentration vve should determine
Km and V rnax for t he drug then ca l culate the
dosing inter va l to get the required Cpss

Phenytoin indication & th. range

Chronic treatrnent of tonic-clonic or partial epilepsy.

Acute treatment of generalized status epilepticus.
Type 1B a ntiarrhythmic.

Treatment of trigemina l neuralgia.

Toxicity : Therapeutic cone 10-20 mg/1

> 20: Ny stagmus
> 30: Ataxia
> 40: Mental cha nges
> 100: Death Free cone 1 - 2 mg/L

Phenytoin pharmacokinetics

Oral bioavailability (F) is -100%.

Salt: factor

Pheny toin Na+ (caps, IV) 0.92

Pheny toin Acid (tabs , susp.) 1.0

Vd = 0.7 L/kg*
Extensive binding ( -90%) to albumin.
Free fraction is 10°/o.
95°/o elimination by liver

* f or obese
Vd = 0. 7 Ukg [IBW + 1.33 (TBW- IBW)]

•!• A steady-state trough total phenytoin serum concentration should be measured after
steady-state is attained in 7-14 days. Sample serum levels 7 to 10 days following each
dosage change to assess.
 •!• Half-life: 7 to 42 hours (average= 24 hours).
•!• The maximum single oral dose should not exceed 400 mg. Divided doses increase
bioavailability as well as decrease potential for GI side effects.
•!• The maintenance dose is started 18-24 hours after the loading dose.
•!• maintenance dose normally given in divided doses q8-12h
•!• Total phenytoin concentration (cheap and fast) is the mainstream ofTDM when plasma
protein-binding abnormalities are absent.
•!• Free concentration is required in case of disease affecting the albumin amount in body as
in case of:
•!• 1-hypoalbuminaia (liver disease)
•!• 2-ESRD or dialysis
•!• 3-geriatric

• Cnorm ar = Cobserved/ [(X . Albumin) + 0.1]

X Population
0.2-0.25 Serum albumin s 3 g/dl

0.1 ESRD (CrCI < 15 ml/min), dialysi s

• A lso ca lled corrected phenytoin concentration

If the protein binding measureme nt in lab were done in room temp

25C, use 0.25 (clincalc). if the protein binding measurement in lab were
done in body temp 37C,use 0.2 (medscape).

In practice, body temperature is the preferred method.

Case Study
• A patient with ESRD has a reported phenytoin-related adverse drug reaction
and the total phenytoin concentration i s 15 mg/L.

Question 1:

A patient with ESRD has a reported phenytoin-related adverse drug reaction and the total
phenytoin concentration is 15 mg/L. serum albumin concentration was 3 g/dl.

Question 2:

LM is an epileptic patient being treated with phenytoin. He has hypoalbuminemia (albumin = 2.2
g/dL) and decreased renal function (creatinine clearance= 50 mL/min). His total phenytoin
concentration is 7.5 mg/L.

A-Compute an estimated normalized phenytoin concentration for this patient.

B- after 3 days, more decrease in renal function occur (creatinine clearance = 10 mUmin).
Compute an new estimated normalized phenytoin concentration for this patient.
Initial dosage detennination for phenytoin

Parameter Estimate (not including elderly>60 years)

Vmax Adult: 7 mg/kg/day

7-16 years: 9 mg/kg/day
'h-6 years: 1 2 mg/kg/day
Km Adult: 4 mg/L
7-16 years: 6 mg/L
'h-6 years: 6 mg/L
Vd 0.7 L/kg*

Initial dosage determination for phenytoin

Phenytoin adjusted body weight= IBW + 1.33 (TBW- IBW) is used only for loading dose in
obese

AdjBW = IBW + 0.4 (TBW-IBW) may be used for Maintenance dose in obese.

Simplified Table (from literature) for Initial dosage determination

Population Loading Dose Maintenance Dose

Adults 15-20 mg/kg/day 4-6 mg/kg/day

Children (6M-16 years) 15-20 mg/kg/day 5-10 mg/kg/day

Elderly (> 60 years) 3-4 mg/kg/day

Obese patients use adjusted body weight*( LD vs MD)

Significant Reduce this dose by 25-50%
hepatic
impairment

Question 3

TD is a 50-year-old, 75-kg (height = 5 ft 10 inch) male with simple partial seizures who requires
therapy with oral phenytoin capsule. He has normal liver and renal function. Suggest an initial
phenytoin sodium capsule dosage regimen designed to achieve a steady-state phenytoin
concentration equal to 12 mg/L.
Answer 3

1. Estimate Michae/is-Menten constants according to d sease states

and conditions present in the patient. For this individual,
Vm8x = 7 mg/kg/d. For a 75-kg patient, Vmax = 525 mg/d,
Km = 4 mg/L.

2. Compute dosage regimen.

Oral extended phenytoin sodium capsules will be prescribed to this patient (F =
=
1, S 0.92). The initial dosage interval (t) will be set to 24 hours. The dosage
equation for phenytoin is:

428 mg/d,rounded to 400 mg/

A steady-state trough total phenytoin serum concentration should be measured

after steady-state is attained in 7-14 days

Question 4

UO is a 10-year-old, 40-kg, 145 em male with simple partial seizures who requires therapy with
oral phenytoin suspension. He has normal liver and renal function. Suggest an initial phenytoin
dosage regimen designed to achieve a steady-state phenytoin concentration equal to 12 mg/L.

Answer4

1. Estimate Michae/is-Menten constants according to disease states and

conditions present in the patient.
The Vmax for a 7-16-year-old adolescent patient with normal liver and renal
function is 9 mg/kg/d. For a 40-kg patient, Vmax = 360 mg/d: For this individual,
Km = 6 mg/L

2. Compute dosage regimen

Oral phenytoin suspension (F = 1, S = 1). The initial dosage interval (t) will be set
to 12 hours.

Phenytoin suspension 125 mg every 12 hours would be prescribed for the

patient. A steady-state trough total phenytoin serum concentration should be
measured after steady-state is attained in 7-14 days

Dosing based on one available phenytoin Css value

•!• With only one steady state serum level available, you can calculate a value for Vmax if
you assume a value for Km (Note: references assume a value of 4 mg/L for Km)
•!• Vmax =daily dose(mg/day) x (Km/Css + 1)
•!• MD/Vmax (old)=MD/Vmax (new)
•!• This will be required for modification in dose in the Css is out of therapeutic range after
initial dosing.
•!• Changes in the daily maintenance dose should be made in small increments (30-100 mg
maximum)
Graphical method

14

RATE OF 12
ELIMINATI ON
R.Vm
<mo/k o/dovl 10

24 20 16 12 0 4 8 12 16
C55 (m/ 111od K m (rJ't9/liter )

Question 5

After 14 days of dose initiation, the plasma cone was 8 mg/L. the physician need dose
adjustment to reach the plasma cone of 12

Answer: (mathematically or graphically)

•!• Vmax =daily dose(mg/day) x (Km/Css + 1)

•!• Vmax = 600 mg/L
•!• 428/525 = MD/600
•!• The MD= 489 ::::o 500 mg/day
•!• This means to increase the dose by 100 mg daily and measure the plasma cone after 7
days.

Determination of Km and Vmax for phenytoin

There two methods for calculating Km and Vmax for phenytoin.

•!• 1-Linear transformation method (ludden method)

•!• 2-Mullen Method

Both require determination of two steady state concentration corresponding to different two
dosage regimen
1-Linear transformation method

S F".£> V 1Tl.a:x Cp.s.s

T .K:I'n -1- C_p.s.s

S 1--.L> S F L>
.K:rn -1- Cp.s.s = V max Cp .s.s
T T

Rearrange and divide by S, F and Cpss

D = -.Krn D lz- -t- Vmax

z- C_pss sF
T his is straigh t line equation where the slope is - KlTl and the
intercept is Vtnax/sF
Then calcu late the dosing interva l t hat give the required Cpss

Graph for linear transformation method

3.0

2.5
D/T
Intercept = Vmax/SF
0.2

1.5

1.0

0.5

0.0 0 12

The direct linear plot method (Mullen Method)

•!• This method require the knowledge of two different dosing rate and their corresponding
steady state concentration.
•!• Present the steady state concentration points (Cpss) on the left side of the X axis and the
dosing rate "daily dose" on the Y axis
•!• By plotting the two lines between each of the dosing rates and their corresponding steady
state concentration. The two lines will cross at a point.
•!• The value on X axis will be Km and the Value on Y axis will be Vmax
Graph presentation of The direct linear plot method

30
Phonyto•n C"- (f'ng/ L)

Question 6: A 74 kg, 28 year old man is receiving phenytoin for the treatment of seizures. When this
patient was taking a daily oral dose of 250 mg phenytoin tablet, his steady state plasma concentration was
7.2 mg!L. because phenytoin plasma concentration was well below the therapeutic range, the patient daily
dose was increased to 450 mg which resulted in steady state plasma concentration of 30 mg/L. phenytoin
bioavailability is 100% and the Vd is 50 L.

•!• a-Graphically calculate the patient Vmax and Km?

•!• b-Calculate phenytoin half-life in this patient at steady state while taking 450 mg daily?
•!• c-What is the steady state concentration that should be achieved if the dose was 300 mg daily?
•!• d-What is the daily phenytoin dose that should achieve a steady state phenytoin plasma
concentration of 20 mg/ L in this patient?

Question 7: A 25 kg, 14 year old female was admitted to the hospital because of frequent episodes
seizures. She was started on IV phenytoin with loading dose of 5 mg/kg followed by 80 mg phenytoin IV
every 12 hr. at steady state the avg plasma concentration was 8 mg!L. the phenytoin dose increased to 100
mg IV every 12 hr and the steady state concentration was 13.3 mg/L. later on, the phenytoin IV was
replaced by oral solution 225 mg at bed daily of phenytoin which has 100 bioavailability. The Vd is 0.8
Llkg.

•!• a-Graphically estimate the phenytoin Vmax and Km in this patient?

•!• b-What is the avg steady state drug concentration on the oral regimen?
•!• c-Calculate the clearance and the half-life of the drug on the oral regimen?

Question 8: Mr SG is a 58 y/o, 72 inch, 70 kg male, seen recently with symptoms of a lower Respiratory
infection. At this time he had a lesion noted on his Chest X-ray. A lung biopsy revealed a carcinoma with
metastasis to The head, demonstrated via aCT scan. His albumin was 4 gm/1 and serum creatinine 1.0
.Phenytoin therapy was initiated prophylactically at a dosage of 400 mg daily. Two weeks later, the
patient had a grand mal seizure and the phenytoin Cp was5 mg/1. The dosage was increased to 500 mg qd
and 3 weeks later, The phenytoin concentration was 7 mg/1.

•!• a-Using the Ludden method graph, estimate the Vmax and Km for this patient.
•!• b-estimate a dose necessary to achieve a phenytoin concentration of 15 mg/1
Chapter 5: Dosage adjustment in renal & hepatic disease state
Introduction

TBC is the sum of metabolic clearance (kmVd), the renal clearance (KeVd) and other clearance if
found (KxVd).
There is situations in which the drug clearance may change (like age,drug interaction,diseases,
genetic variations).
The change in drug clearance will depend on drug nature:
If the drug is rna inly cleared by metabolism,renaI dysfunction will have no effect on TBC
If the drug is rna inly cleared by excretion,renal dysfunction will have effect on TBC

Metabolic clearance

Metabolic clearance (MC) depend on:

The activity of metabolizing enzyme
Hepatic blood flow (HBF) for drug that are rapidly metabolized by enzyme. As any decrease in
HBF will decrease drug transport to liver and will affect MC.

Variable affecting MC

Age
Liver disease
Drug interactions affecting metabolism
Plasma protein binding of drug (transient effects)
Hormonal effects

Variable affecting renal clearance

Renal dysfunction
Age
Drugs interaction on renal tubules

As the renal clearance depend on GFR on its value, so any changes in renal function (known by changes
in GFR) in will cause a parallel effect on the drug elimination for drug excreted unchanged by kidney

Variable affecting renal clearance

Renal function is usually measured by GFR.

GFR can be estimated by measuring the clearance for substances cleared only by GFR (without
active secretion or tubular reabsorption) example of commonly used substances is inulin, and
creatinine.
The effect of liver disease on TBC

Liver disorder (like hepatitis C,bilharzia isis,alcoholic fatty liver) will affects drug metabolism for
drug mainly excreted by metabolism.
There is no direct relation between the degree of liver dysfunction and the decrease in drug
metabolism.
Sever liver damage must be present before significant change in drug metabolism occur.
Not a II liver diseases affect the pharmacokinetics of the drugs to the same extent.
Oral drug bioavailability may be increased by liver disease due to decrease first-pass effects, or
decrease activity for prodrug by decreased drug activation

Child-pugh classification

The Chi ld-P'l_-ah c..I:.!C.si_fi c.ation

As.sc::::iSttlc:nl :O.:gec oC abo01 r.uc:alily Sccn o:

Enc:cph.a.lopa.thy None 1
Moderate 2
Se-vere 3
A.set tes Ahent ]
Slight 2
Moderat-e 3
BiJicubin (mg/d.L) <2 1
2.1-3 2
>3 3
Albumin (g/d.L) >3.5 1
2 8-3 5 2
<2.8 3
Prothroo:nbin Tir:n e 0-3.9 J
(seconds ::;. coottol) 4-6 2
>6 3

Total Score Grou Severi

5-6 A Mild
7-9 B
10-15 c

Drug significantly affected in chronic liver disease

Cefoperazone Chlordiazepoxide
Chloramphenicol Diazepam
Erythromycin Hexobarbital
Metronidazole Lidocaine
Meperidine Metoprolol
Pentazocine Propranolol
Tocainide Theophylline
Verapamil Promazine

Hormonal Influence

Hormones can also affect the rate of metabolism.

In hyperthyroid patients, the rate of metabolism of many drugs is increased, for example, the
rates for theophylline, digoxin, and propranolol.
In hypothyroid disease,the rate of metabolism of these drugs may be decreased
Active Drug and the Metabolite

For some drugs,both the drug and the metabolite contribute to the overall therapeutic
response of the patient to the drug. The concentration of both the drug and the metabolite in
the body should be known.

Two options may occur as a result of a change in liver function

(1) when the drug is more potent than the metabolite,the overall pharmacologic activity will increase in
the hepatic-impaired patient because the parent drug concentration will be higher

(2) when the drug is less potent than the metabolite,the overall pharmacologic activity in the hepatic
patient will decrease because less of the active metabolite is formed.

The effect of renal disease on TBC

Important for drug mainly excreted unchanged in urine

Examples of disorders which affect renal function (Pyelonephritis, DM, Nephrotoxic drugs,
chronic uncontrolled hypertension)
the degree of renal dysfunction will cause a parallel change in GFR.
The fraction of rena I function remaining (KF) will have a direct relation with the value of G FR
This means that dose adjustment in renal dysfunction is possible after known KF.

Table 3. Renally Excreted Drugs and Drugs That Require Dosage Adjustmentsa
• ACEis and ARBs • Hyp:lglycemic drugs (e.g., acarbose, metformin,m litol,
• Mbfungals (e.g.,amphoterictn,fluconazole, nateghnkle,repaglrnlde,frrst·generabon sulfonyklreas
ftucytosine, itraconazole, vooconazOie) and selecled second·generabon suHonytureas
• Mbgout drugs (e.g.,allopurinol,roldl ne) [ghmeJ)ride, gl)turide)l
• Mtrtubercutosls drugs (e.g.,etllambutol,INH,nfampln) • Most penlcinins and cephalosporin anbbiotJcs
• MWiraldrugs (e.g.,acyciOVtr.amantadrne. foscarnet • NSAJOs (e.g.,ibuprofen.ketorOiaC. naproxen)
ir ,rimanladine, valacyclovi • Opiold drugs (e.g., code1ne, meperidine,morphine,
• Chemotherapeutic drugs propoxyphene)
• DigOxin • SuHamelhoxazolelttfmethoprim
• Auoroquinolone antibtotJcs (e.g.,ciprotloxactn, • vancomycin IV
levofloxacin) • Others, including cetiril•ne,duloxetine,enoxaparin,
• H2 anlagooisiS (e.g.,e metidine,famobdine, fexofenadine,gabapenbn, HMG·CoA reductase inhlbilors
rallltrdrne) (statins),lllllrum.metoelopram de,methOtrexate,
• Hydrophil( bela·blockers (e.g.,alenolol,solalol) nitrofurantoin,tetracyclme,tirofiban,lramadol

Dose adjustment for renal dysfunction

The dose required in renal failure can be calculated as following:

Dfail= Dnorm [f (kF-1)+1]

Dnorm: normal dose in adults

f: fraction of drug excreted unchanged in urine
 KF: The fraction of renal function remaining(KF)

Dose adjustment for renal dysfunction

The new half life in renal failure can be calculated

as following:

T1/2 fail= TI I 2nor7nal

[f(KF-1)-t-1]

f: fraction of drug excreted unchanged in urine

KF: The fraction of renal function remaining(KF)
Alsothe following equation can be obtained.
Dfail /Clfail= Dnorm /CJnorm
Dnorm X t1/2 norm= Dfail X t1/2 fail

Calculation of (KF)

The KF value can be calculated from the

following:

KF= GFRfail CrCl.fail

GFRnorm CrCl.norm

CrCI : Creatinine clearance

Creatinine clearance

In clinical practice,creatinine clearance is used to measure GFR (preferred than inulin).

Creatinine is produced naturally by the body (creatinine is a breakdown product of creatine
phosphate, which is found in muscle). It is freely filtered by the glomerulus,but also actively
secreted by the peritubular capillaries but insignficant amount.

Renal impairment classification & creatinine clearance

r- -
Group Description Estimated Creatinine Clearance (ml/min)
1 Normal renal function >80 m/lmin
2 Mild renal impairment 50-80 m/m
l in
3 Moderate renal impairment 30-50 ml/min
4 Severe renal impairment <30 m/lmin

Measurement of Creatinine clearance

A- 24 hr urine collection:

UcrX24hrvolurnern l / mtn
.
CrCI=
PcrX60X24

Twenty-four hour urine collection to assess creatinine clearance is no longer widely performed, due to
difficulty in assuring complete specimen collection as need to calculates the amount of creatinine
excreted over a 24-hour period

B- using Cockcroft-Gault formula

For male
CrCI= (140 - age )( wt)
72XCrs(mg I dl)
For female
CrCI=O.SS X (l 40 -age)(wt)
72XCr,(mg / dl)
Unit is ml/min
Crs is seru m creati nin e, wt ideal body weight in Kg

Crcl for obese people

Obese if BMI 30 or ABW/IBW 1.3 BMI= wt(kg)/he(m)

CrCI = [(140- age) x AjBW] I (Scr x 72)

Note: (Multiply result by 0.85 for females)

AjBW =adjusted body weight:

AjBW = IBW + 0.4( ABW- IBW)

 ®
Some studies have shown that utilizing the adjusted body weight improves accuracy in estim ating the
creatinine clearance in the elderly population.

Crcl for pediatric

Ideally a 24 hour urine collection and a mid-point serum creatinine should be obtained. This
method is the most accurate clinical measure of creatinine clearance.

Schwartz equation:

This method is good as a general estimate

CrCI (ml/min)= [length (em) x k] I Scr

(Patient population: infants over 1week old through adolescence (18 years old))

k = 0.45 for infants 1to 52 weeks old

k = 0.55 for children 1to 13 years old
k = 0.55 for adolescent females 13-18 years old
k = 0.7 for adolescent males 13-18 years old

Nomogram for creatinine clearance (adult)

Cleao rCJonc:•

,:..;:
(...-. L,/ n

100

00

..,;>
.:>0
4U

30

The nomogram method estimates Crcl on the basis of age, weight, and serum creatinine

To use the nomogram,connect the patient's weight on the second line from the left with the patient's
age on the fourth line with a ruler. Note the point of intersection on Rand keep the ruler there. Turn the
right part of the ruler to the appropriate serum creatinine value and the left side will indicate the
clearance in ml/min.

The Wagner Method

The methods for renal dose adjustment discussed in the previous sections all assume that Vd is
unchanged. These assumptions are convenient and hold true for many drugs.
However,if Vd is changed, Wagner method can be used for calculation of patient half-life.
 ®
The method assume a linear relationship between Ke and Crcl for all drug after collecting data
from populations

K = a + b (Crcl)

The value for a and bin the equation will depend on the drug type. The values of a and bare
determined statistically for each drug from pooled data on uremic patients.

K = 0.00293 (Cicr) + 0.014 for gentamycin

Creatinine clearance (mUmin)

Dialysis & drug clearance

Dialysis is required in ESRD for removal of waste from body. It may be required from once every
2 days to 3 times a week, with each treatment period lasting 2 to 4 hours.
Dosing of drugs in patients receiving hemodialysis is affected greatly by the frequency and type
of dialysis machine used and by the physicochemical and pharmacokinetic properties of the
drug.

Blood rerr10Yi!d ror

Factors affecting drug dialysis

Protein binding Bound form of the drug is not dialyzed

MoiWt. >500 D are not dialyzed (vancomycin)

Vd The larger Vd , the slower dialysis

The dialysis machine character

Blood flow rate to machine The higher flow rate in machine,the more dialysis
(changeable)
dialysate Composition of the dialysate
Dialysis membrane Permeability character and surface area

Dialysis clearance

Q(
Cl0

Where:

C a= drug concentrations in arterial blood (blood entering kidney machine)

C v =drug concentration in venous blood (blood leaving kidney machine)
Q =rate of blood flow to the dialysis machine
Cl D =dialysance (dialysis clearance).

Dosing for patient on dialysis

• In dosing of d rugs for pati ents on dia lysi

s,the average plasma drug concent:rat:ion of a
pat:ient: is given by

• In pract:ice,If Cl 0 Is 30% or more of Cl T•

adjustment i s usually made for t he amount
of drug lost: in dialys is.

Special consideration:

The loading drug dose is based on Vd of the patient. In renaI dysfunction, Vd is not altered significantly,
and therefore that the loading dose of the drug is the same as in subjects with normal renal function.

The maintenance dose in multiple drug administration will be changed by (1) decreasing the
maintenance dose,(2) increasing the dosage interval.
Chapter 6: Vancomycin TDM

Phannacokinetic model (intennittent IV infusion)

•!• Following repeated administration of these short IV infusion, the drug will accumulate in
the body until steady state is achieved.
•!• At steady state, the maximum and minimum plasma concentration will be constant ifthe
dose, infusion duration, dosing interval are kept constant.

lO

,L- ------ ------ ------ ------ --

Ko = infusion rate = dose/t' (m.g7IW:'

Vancomycin Concentration Graph Over Time

50.0
::::;- • Duration of infusion (T,.,.,.....>

... 37.
"'"
=
25.0
(Q

12 5
c::
0

0
0.0
0 10 20 30 ..10
Tome (nours)
Fonnulation and stability

•!• As vial powder in 5oomg or 1 gm amount.

•!• in Prior to reconstitution, store dry powder at 20° to 25°C .
•!• Reconstitued in 10 ml of sterile water, NS, or D5W 500 mg or 20 ml to 1 gm. The 10 ml
is diluted with diluent to 100 ml. and the 20 ml is diluted in 200 ml of diluent.
•!• Reconstituted solutions of vancomycin are chemically stable at room temperature for 24
hours or in a refrigerator for 96 hours without significant loss of potency

Routine dosing

•!• In adjusting the dose make approximation to the nearest available bottle in the market for
vancomycin it is 500 mg, 750 mg, 1 gm, 125omg, 1.5 gm, 1750 mg, 2 gm, 2.5 gm.

• AUC-dependent killing (AUC/MIC)

10 ---------------- 10 ----------------10 ----------------
g 0 g
j s r- 6
0
8 6 0
------------------- 0

6 r- §gEt
:J:
4r o o£
J2 r- l:J'S
010------ --------IT
100
0 I I
10
I
100
I
1000
O '--'1----LI----LI----1'--
0 25 50 75
..1-.J
100
1 24·Hour AUC/MIC Pcook/MIC Time obovo MIC

colony-forming unit (CFU or cfu) is a mea sure of viable bacterial or fungal cells. In direct
microscopic counts where all cells,dead and living, are counted,but CFU measures
only viable cells.

Vancomycin phannacodynamics profile

AUC-dependent killing (AUC/MIC)

Predi ctors of Bacterial Eradication:

Pha rmacokinetic/ Pharrn acodynamic Profiles

Peai</MIC T> MIC 24h-A UC/MIC

I..LIC

.....c.

- Arninoglycosides - Beta-l actarns - A zith.-ornycin

- Clindarnycin - Quinolones
- Ery1h.-ornycin - Vancomy cin
- Linezo l id
 ®
•!• Pharmacokinetic and pharmacodynamic studies have concluded that maximizing the area
under the curve/MIC (AUC/MIC) ratio when dosing vancomycin gives optimal efficacy
for treating S. aureus infections.
•!• An AUC/MIC ratio of 2400 has been advocated as a target to achieve clinical outcome
with vancomycin.

Vancomycin pharmacokinetics

•!• Oral bioavailability (F) is POOR (<5%).

•!• PO Indication: Gut wall inflammation (Clostridium difficile-associated colitis)
•!• only given intravenously when treating systemic infections
•!• Volume of distribution (Vd)0.7 Llkg (ABW) with (range 0.4-1.0 Llkg).
•!• In Obese patients (ABW >30% IBW), Vd= 0.7 Llkg (ABW)
•!• The volume of distribution is variable and depends on many things such as fluid status,
disease state (hematologic malignancy), and age.
•!• Plasma protein binding is55% (non significant change).

Vancomycin is almost completely eliminated unchanged by the kidney. Reports of

accumulation in renal failure

•!• k = 0.00083 [ClCr] + 0.0044

•!• Cl=K X Vd
•!• Clvan = 0.689 [ClCr] + 3.66
•!• Clcr use IBW if IBW<ABW

use ABW if ABM<IBW

use AjBW if obese

Condition affecting half-life

•!• Not significantly removed by dialysis.

•!• The elimination half-life is approximately 6 hours, and can be prolonged up to 2 days in
patients with renal failure.

Premature neonates (gestational age 32 weeks ) 10

Full-term neonates 7
Infants e1month - <1 year) 4.1
Children (2.5-11 years) 5.6 ± 2.1
Adults (16-65 Years) 7.0 ± 1.5 --_-
Adults with renalImpairment 32 ± 19
(CrCI10-60 ml/min)
Geriatrics (>65 years) 12 ± 0.8
Major body burns (>30%-40% BSA) 4
Vancomycin dosing guidelines

According to ASHP and IDSA "infectious diseases society of America":

•!• 1-AUC/MIC >400 (correlates with successful clinical outcomes).

•!• 2-Trough cone. can be used as a surrogate marker for AUC.
•!• 3-Troughs should be above 10 mg/L to minimize resistance
•!• 4- "10-15" mg/L for UTI and skin infection (MIC < 1).
•!• 5- "15-20" mg/L for complicated infections due to MRSA (endocarditis, meningitis,
HCAP "health care-associated pneumonia") (MIC < 2).
•!• 6-The target peak plasma concentration (Cmax) is 30-40 mg/L.
•!• 7-For Infections with MIC 2>2, consider an alternative therapy.

Loading & pediatric dose

•!• A loading dose of25-30 mg/kg may be considered (should be rounded to the nearest 250
mg) specially for critically ill patient.
or
•!• LD = Cmax x Vd

Pediatric Patients maintainance dose:

•!• The usual intravenous dosage ofvancomycin is 10 mg/kg per dose given every six hours.
Each dose should be administered over a period of at least 60 minutes.

Infusion time

Infusion-related events "red man syndrome" are related to both concentration and rate of
administration ofvancomycin. Concentrations of no more than 5 mg/mL and rates of no more
than 1gm/hr are recommended in adults. Also minimized by rotating the sites of infusion.

Single doses should not exceed 3 g

Dose Infusion Time

500 mg 0.5-1 hr.
1,000 mg 1 hr.
2,000 mg 2 hr.
3,000 mg 3 hr.
Vancomycin monitoring

Response to therapy

•!• Markers of infection (fever, WBCs, chest X-ray).

•!• Culture and sensitivity results

Vancomycin Trough Levels may be clinically indicated when (e.g.):

•!• Duration of therapy longer than 5 days.

•!• Unstable renal functions.
•!• Existing risk of nephrotoxicity
•!• At least one trough at steady state (just before the 4th dose). Repeat if deemed clinically
appropriate.
•!• Once weekly monitoring is recommended in hemodynamically stable patients.

Adverse Reactions:

•!• Nephrotoxicity
•!• Ototoxicity.
•!• Infusion reactions (e.g. Red Man Syndrome).

Red man syndrome :

•!• If vancomycin is administered too quickly or if it is too concentrated, it is known to cause

a histamine-like reaction known as red-man syndrome (erythroderma in neck, hand with
hypotension) and may also cause thrombophlebitis.
•!• RMS can occur after infusion of the first dose of vancomycin or at any time during
vancomycin therapy.
•!• It can appear as early as 4-10 minutes after the start of infusion or can occur after the
infusion has completed.

Vancomycin induced nephrotoxicity (VIN)

•!• The exact mechanism of vancomycin-induced nephrotoxicity (VIN) has not been fully
elucidated.
•!• Reversible nature suspected if an increase in the SCr level of >0.5 mg/dL or 50 percent
from baseline.

Risk factors:

•!• Advanced age.

•!• Co-administration of other nephrotoxic agents.
•!• Longer treatment course.
•!• Higher trough cone. (30-65 mg/L)
Monitoring:

•!• Vanco. trough and [Cr] at least weekly in hemodynamically stable patients.
•!• More frequent monitoring (daily) in high risk patients.

Vancomycin induced ototoxicity (VIO)

•!• less commonly reported as an adverse drug event compared to VIN.

•!• VIO can either be reversible or irreversible, depending on the vancomycin peak serum
concentrations.
•!• Reversible ototoxicity is generally associated irreversible damage with greater peak than
80 mg/L.
•!• Therefore, if a patient starts complaining of loss of acuity to high-frequency sounds and
tinnitus, which are regarded as prominent signs of VIO, vancomycin therapy should be
discontinued.

Approaches for vancomycin dosing

Empiric I
Dose by level

A- initiation of vancomycin dosing "Empiric"

•!• To Initiate an appropriate dose

•!• Determine loading dose
•!• Determine maintenance dose
•!• Monitor the patient for patient peak and trough value
Indication Goal Vanc omyci n level *
- -

Peak Trough
UTI, Skin infection 25-40 10-15

HCAP, endocarditi s 25-40 15-20

meninigitis

A- initiation of Van. dosing "Empiric"

Steps:

•!• 1-estimate K and vd for population

•!• 2-decide peak and trough value
•!• 3-calculate 1:= dosing interval (hr.)
o Ko= infusion rate = dose/t' (mg/hr.)
o t' =infusion time (hr.) "no more than lgm/hr"
Case study 1: Vancomycin TDM

OPatient: FG
D Age: 89 Vancoinycin Dose Per Pharinao/
D Height: 160 em
O Weight: 49.2 Kg
O Gender: F
0 [Cr]: 0.9 mg/dl
D indication: HCAP

(peak value 25-40 mg/L; trough 15-20 mg/L).

Recommend a vancomycin dosing regimen for this patient using

Loading dose.

Case 1: Answer

1. Calculate IBW? IBW = 51.8 Kg, so use, ABW 49.2

2. Estimate creatinine clearance:

CrCI= 32.9 mllmin

2. Estnnate elimination rate constant (ke) and half-life (t 112).

K= 0.0317 h- 1
Tl/2= 21.85 hr

2. Estnnate volmne of distribution (V): The patient does not have

any condition that may alter the normal Vd value (0.7 L/kg)

Vd= 0.7 x ABW (49.2)

Vd=34.4 L

4. Choose desired st eady-state serum concentrations.

Set Cssmax = 37.5 J-lg/mL and Cssmin = 17.5 J.l-g/mL
5. Use intermittent intravenous infusion equations to compute dosing
interval.
T= 25 hr= 24 hr
In this case, the dosage interv al wou ld be rounded to 24 hours.
6. Use intermittent intravenous infus i on equations to compute dose.
Ko= 710 mg =
750 mg

7. The prescribed maint:enance dose ""ould be: 750mg over 1 hr.

every 24 hours.

Loading Dose: 25-30 mg/kg

 •!• = 25-30 mg/kg x 49.2 kg1250-1500 mg, Infuse over 75-90 min
•!• The final recommendation is 1500 mg over 90 min now, then after 24 hr, use 750 mg
infused on 1 hr every 24 hr.
•!• Check expected peak and trough by globalrph

Case 2: Vancomycin initiation therapy

I:JPatient: JM
I:JAge: SO Vancon:1ycin Dose Per Pharn:1acy
I:JHeight: Sft 11i
n I:JWeight: 70
Kg I:JGender: M
I:J[Cr]: 0.9 mg/dl (stable for 5 days)
Dlndication: Cellulitis

Recommend a vancomycin dosing regimen for this patient

using loading dose.
( N ote: Set pea k= 30 f.lg / m and t rough = 1 2 f.lg/m)l.

Case 2: answer

Dosing weight ?IBW= 75.3 kg so use ABM= 70 mg

Estimate creatinine clearance:

•!• 97 ml/min

Estimate elimination rate constant (ke) and half-life (tl /2).

•!• K=0.087 h" 1

•!• Tl/2= 8 hr

Estimate volume of distribution: 49 L

•!• Interval = 10.512 hr

•!• Ko= 965 mg1000 mg
•!• LD= 25 x 70= 1750 mg over 2 hour infusion

The prescribed maintenance dose would be:1000 mg every 12 hours over 1 hr infusion

Dose adjustment at steady state

•!• 1-measure: At steady state, take two samples (for observed peak and observed trough)
and measure concentrations and determine the time in between.
•!• 2-calculate the true peak and true trough concentration
•!• 2-determine K and Vd for this patient
•!• 3- decide: decide the required peak and trough
 ®
•!• 4-claculate the required Ko, T for this patient: adjust the dose if required bases on patient
specific parameters

Dose by level

•!• Two samples at steady state (before the 4 dose) are taken one for peak (1 hr or more after
the end of infusion to allow adequate time for drug distribution) and the other for trough
(30 min or more before the dose administration).
•!• K= ln(Cl!C2)/L1 t
•!• C1 =observed peak
•!• C2 = observed trough
•!• L1 t =difference in time between C1 and C2 within the same dosing interval
•!• Then determine true peak and true trough
•!• C1 = Cpeak x e<· K x t2)
•!• where Cpeak =true peak (end ofvanco infusion).
•!• Ctrough = C2 x e( ·K x t3)
•!• where Ctrough = true trough.
•!• t2 = time between peak drawn and the end of the infusion
•!• t3 =time between trough drawn and true trough

Example

•!• AJ has HCAP with Height= 5'3", Weight= 130 lbs, SCr = 0.9 mg/dL
•!• AJ receives vancomycin 1250 mg once daily at 10:00 AM. A peak level drawn on day 4
oftherapy at 2:00PM was 30.5 mg/L and a trough level drawn on day 5 of therapy at
8:30AM was 13.0 mg/L.
•!• Make dose adjustment required to achieve the desired trough cone above 15 mg/L.

Answer:

•!• Ll t=18.5
•!• K= 0.046 hr-1
•!• True peak= 33.44 mg/L
•!• Trough trough= 12.13 mg/L
•!• Vd (using Cmax equation) = 54.6 L
•!• Then decide Cmax =37.5 and Cmin=17.5 mg/L
•!• Calculate 1: and Ko
•!• 750 mg infused over 60 min repeated every 12 hr may be advised
 Chapter 7: Bioavailability & Bioequivalence

Introduction:
A multisource drug product is a drug product that contains the same active drug substance in the
same dosage form and is marketed by more than one pharmaceutical manufacturer. Single-
source drug products are drug products for which the patent has not yet expired or has certain
exclusivities so that only one manufacturer can make it. Single-source drug products are usually
brand-name (innovator) drug products. After the patent and other exclusivities for the brand-
name drug expires, a pharmaceutical firm may manufacture a generic drug product that can be
substituted for the branded drug product. Since the formulation and method of manufacture of
the drug product can affect the bioavailability and stability of the drug, the generic drug
manufacturer must demonstrate that the generic drug product is bioequivalent and therapeutically
equivalent to the brand-name drug product.

Drug product selection and generic drug product substitution are major responsibilities for
physicians, pharmacists, and others who prescribe, dispense, or purchase drugs. To facilitate
such decisions, the U.S. Food and Drug Administration (FDA) publishes annually, in print and
on the Internet, Approved Drug Products with Therapeutic Equivalence Evaluations, also known
as the Orange Book (www.fda.gov/cder/orange/default.htm). The Orange Book identifies drug
products approved on the basis of safety and effectiveness by the FDA and contains therapeutic
equivalence evaluations for approved multisource prescription drug products. These evaluations
serve as public information and advice to state health agencies, prescribers, and pharmacists to
promote public education in the area of drug product selection and to foster containment of
health care costs. The following definitions are from the 2003 Orange Book, Code of Federal
Regulations.

Defmitions
Bioavailability. Bioavailability means the rate and extent to which the active ingredient or active
moiety is absorbed from a drug product and becomes available at the site of action. For drug
products that are not intended to be absorbed into the bloodstream, bioavailability may be
assessed by measurements intended to reflect the rate and extent to which the active ingredient or
active moiety becomes available at the site of action.

Bioequivalence requirement. A requirement imposed by the FDA for in-vitro and/or in vivo
testing of specified drug products, which must be satisfied. Bioequivalent drug products. This
term describes pharmaceutical equivalent or pharmaceutical alternative products that display
comparable bioavailability when studied under similar experimental conditions. For systemically
absorbed drugs, the test (generic) and reference listed drug (brand-name) shall be considered
bioequivalent if: (1) the rate and extent of absorption of the test drug do not show a significant
difference from the rate and extent of absorption of the reference drug when administered at the
same molar dose of the therapeutic ingredient under similar experimental conditions in either a
single dose or multiple doses; or (2) the extent of absorption of the test drug does not show a
significant difference from the extent of absorption of the reference drug when administered at
the same molar dose ofthe therapeutic ingredient under similar experimental conditions in either a
single dose or multiple doses and the difference from the reference drug in the rate of
 ®
absorption of the drug is intentional, is reflected in its proposed labeling, is not essential to the
attainment of effective body drug concentrations on chronic use, and is considered medically
insignificant for the drug.

When the above methods are not applicable (eg, for drug products that are not intended to be
absorbed into the bloodstream), other in-vivo or in-vitro test methods to demonstrate
bioequivalence may be appropriate. Bioequivalence may sometimes be demonstrated using an
in-vitro bioequivalence standard, especially when such an in-vitro test has been correlated with
human in-vivo bioavailability data. In other situations, bioequivalence may sometimes be
demonstrated through comparative clinical trials or pharmacodynamic studies.

Bioequivalent drug products may contain different inactive ingredients, provided the manufacturer
identifies the differences and provides information that the differences do not affect the safety
or efficacy of the product.

Brand name. The trade name of the drug. This name is privately owned by the manufacturer
or distributor and is used to distinguish the specific drug product from competitor's products (eg,
Tylenol, McNeil Laboratories).

Chemical name. The name used by organic chemists to indicate the chemical structure of
the drug (eg, N-acetyl-p-aminophenol).

Generic name. The established, nonproprietary, or common name of the active drug in a
drug product (eg, acetaminophen).

Purpose of Bioavailability Studies

Bioavailability studies are performed for both approved active drug ingredients and therapeutic
moieties not yet approved for marketing by the FDA. New formulations of active drug
ingredients must be approved by the FDA before marketing. In approving a drug product for
marketing, the FDA ensures that the drug product is safe and effective for its labeled indications
for use. Moreover, the drug product must meet all applicable standards of identity, strength,
quality, and purity. To ensure that these standards are met, the FDA requires
bioavailability/pharmacokinetic studies and, where necessary, bioequivalence studies for all drug
products (FDA Guidance for Industry, 2003). Bioavailability may be considered as one aspect of
drug product quality that links in-vivo performance of the drug product used in clinical trials to
studies demonstrating evidence of safety and efficacy.

For unmarketed drugs that do not have full NDA approval by the FDA, in-vitro and/or in-vivo
bioequivalence studies must be performed on the drug formulation proposed for marketing as a
generic drug product. Furthermore, the essential pharmacokinetics of the active drug ingredient
or therapeutic moiety must be characterized. Essential pharmacokinetic parameters, including the
rate and extent of systemic absorption, elimination half-life, and rates of excretion and
metabolism, should be established after single- and multiple-dose administration. Data from
these in-vivo bioavailability studies are important to establish recommended dosage regimens
and to support drug labeling.
 ®
In-vivo bioavailability studies are also performed for new formulations of active drug ingredients
or therapeutic moieties that have full NDA approval and are approved for marketing. The
purpose of these studies is to determine the bioavailability and to characterize the
pharmacokinetics of the new formulation, new dosage form, or new salt or ester relative to a
reference formulation.

In summary, clinical studies are useful in determining the safety and efficacy of drug products.
Bioavailability studies are used to define the effect of changes in the physicochemical properties
of the drug substance and the effect of the drug product (dosage form) on the pharmacokinetics
of the drug. Bioequivalence studies are used to compare the bioavailability of the same drug
(same salt or ester) from various drug products. Bioavailability and bioequivalence can also be
considered as performance measures of the drug product in-vivo. If the drug products are
bioequivalent and therapeutically equivalent (as defined above), then the clinical efficacy and the
safety profile of these drug products are assumed to be similar and may be substituted for each
other.

Figure 1: Absorption of the sam e active pharmaceutical ingredient after adminisuation

in r:v·.o different salt preparations

..
<
-
"' c.....
c:: i1
-... ......
G.astrk; f luod "'
a :=!.:
I»

0 Olfusaon and absla<Ji ...

c::r •
....
----4·· .. 0
0 -
.
i
- Acln. substance
G) Sail m<»aty I
<:) Sail m<»aty II

In this graph p..-oduct B,which has lower F than p..-oduct A,may not have
any phannacological effect.

200r---------------------------------------------------,

MEC

"E'
..m
c..

Time (llarl
Relative and Absolute Availability
Relative (apparent) availability is the availability of the drug from a drug product as compared to a
recognized standard formulation, usually a solution of the pure drug evaluated.
The area under the drug concentration-time curve (AUC) is used as a measure of the total
amount of unaltered drug that reaches the systemic circulation. The AUC is dependent on the
total quantity of available drug, FD 0, divided by the elimination rate constant, k, and the
apparent volume of distribution, V D· F is the fraction of the dose absorbed. After IV
administration, F is equal to unity, because the entire dose enters the systemic circulation.
Therefore, the drug is considered to be completely available after IV administration. After oral
administration of a drug, F may vary from a value of 0 (no drug absorption) to 1 (complete drug
absorption).

The relative availability of two drug products given

at the same dosage level and by the same route
of administration can be obtained using the
following equation:

AUCa
Relative availability=
AUCb

If use different dose of the two drugs:

Relative availability= AUCa! Da

AUCb / Db

Urinary drug excretion data may also be used to

measure relative availability, as long as the total
amount of intact drug excreted in the urine is
collected. The percent relative availability using
urinary excretion data can be determined as
follows:
A u oo ( a )
Relative availability=
A u oo (b)

\Nhere Au is the total amount of drug collected in

urine

Conditions under which the bioavailability is important:

• In order to exert a pharmacological effect, drug cone in the plasma must exceed its
minimum effective cone (MEC).
• If the plasma cone exceeds the MEC the duration of effect will normally last until the
cone falls below the MEC.
 In this graph product B, which has lower F than product A, may not have
any pharmacological effect.
200 r-----------------------------------------------

Time (hr)

Methods for Assessing Bioavailability and Bioequivalence

1- Plasma drug concentration

•!• -Time for peak plasma (blood) cone. (t max)

•!• -Peak plasma drug concentration (C max)
•!• -Area under the plasma drug concentration-time curve (AUC)

Tmax
•!• When comparing drug products for bioequvalence, t max can be used as an approximate
indication of drug absorption rate. The value for tmax will become smaller (indicating
less time required to reach peak plasma concentration) as the absorption rate for the drug
becomes more rapid
Cmax

•!• C max provides indications that the drug is sufficiently systemically absorbed to provide
a therapeutic response (intensity).
•!• In addition, C max provides warning of possibly toxic levels of drug. The units of C max
are concentration units (eg, mg/mL, ng/mL).
•!• Although not a unit for rate, C max is often used in bioequivalence studies as a measure
for the rate of drug bioavailability

AUC

•!• The area under the plasma level-time curve, AUC, is a measurement of the extent of drug
bioavailability. The AUC reflects the total amount of active drug that reaches the systemic
circulation
•!• The AUC can be determined by a numerical integration procedure, such as the
trapezoidal rule method. The units for AUC are concentration time (eg, g.hr/mL).
 Peak Conc ent ration

Area under the

Curve (AUC)

Time (hr")

Calculation of the AUC (linear trapezoidal rule):

The AUC is approximated as the sum of a
number of trapezoids, into which the area
under the curve has been divide in addition to
the area of tail. The area of each trapezoid is:
Area = ( a+b ) . W
2

a b

w
 The total AUC is found by summing all trapezoids, a nd adding the
arca under the tail of Lhc curve.
8

C2
:::;- 6
.......
.."§".
r::
0
·.;:::: 4
.s
r::
C1J
u
r::
8
E2
;;";':' The tail
of the
curve
co
OL- ---- -- -- =----- ---- --
0.0 1.0 2.0 3.0 4.0
Time (hr)

AUCo -+tlast = S(t;.1 - 1;) . ( Ci + C;.1 )/2

c:
AUCttast = CtastiA z
0
._
cQ)
(.)
c:
0
<....>

•!• Where Clast is the last measured concentration and K is elimination rate constant.
•!• The total area under the curve is the sum of all trapezoids plus the area of the tail.

AUC=( l/2)(CO+Cl)(tl-t0)+(1/2)(Cl +C2)(t2-tl) +...... +area of tail.

2-Urinary drug excretion

•!• Urinary drug excretion data is an indirect method for estimating bioavailability. The drug
must be excreted in significant quantities as unchanged drug in the urine in significant
amount. In addition, timely urine samples must be collected and the total amount of
urinary drug excretion must be obtained.
•!• The total cumulative amount of drug excreted in urine is directly proportional to the total
amount of drug absorbed.
Parameters included are:

•!• -Cumulative amount of drug excreted in the urine (Au)

•!• -Rate of drug excretion in the urine (dA uldt)
•!• -Time for maximum urinary excretion (t)

Aeon The cumulative amount of drug excreted in the urine

•!• Acou, is related directly to the total amount of drug absorbed. Experimentally, urine
samples are collected periodically after administration of a drug product.
•!• A graph is constructed that relates the cumulative drug excreted to the collection-time
interval. The relationship between the cumulative amount of drug excreted in the urine
and the plasma level-time curve is shown in . When the drug is almost completely
eliminated (point C), the plasma concentration approaches zero and the maximum
amount of drug excreted in the urine, A co u, is obtained.

dA u/dt. The rate of urinary drug excretion

•!• Because most drugs are eliminated by a first-order rate process, the rate of drug
excretion is dependent on the first-order elimination rate constant k and the
concentration of drug in the plasma C p.
•!• When urine sample are collected pe1iodically, the urinary drug excretion rate time
profile should have the same shape of the plasma concentration time profile. where ,
the maximum rate of drug excretion, (dA u/dt)max, is at point B, corresponding to
C max in plasma concentration time curve

-Time for maximum urinary excretion (t)

•!• The time for maximum urinary excretion will correspond to the Tmax in plasma
concentration time curve
•!• As shown in the following graph point D will be similar to Tmax

Causes for Bioavailability and Bioequivalence Problems

-Drug products that have a high ratio of excipients to active ingredients (eg, greater than 5:1).
-Specific inactive ingredients (eg, hydrophilic or hydrophobic excipients and lubricants) either
may be required for absorption of the active drug ingredient may interfere with such absorption.
"* -The degree of absorption of the active drug ingredient (eg, less than 50%, ordinarily in
comparison to an intravenous dose)
-There is rapid metabolism of the therapeutic moiety in the intestinal wall or liver during
the absorption process (first pass metabolism),
-The therapeutic moiety is rapidly metabolized or excreted, so that rapid dissolution and
absorption are required for effectiveness.
-The active drug ingredient or therapeutic moiety is unstable in specific portions of the GI
tract and requires special coatings or formulations to ensure adequate absorption.
Criteria for waiver of bioavailability requirements:
The in vivo bioavailability requirements are waived by the FDA if the drug product meets one of
the following criteria:
-Preparations intended for IV use or topical preparation intended for local effect.
-Oral dosage forms not intended for systemic absorption such as antacids and radiopaque
media or products administered by inhalation as a gas or vapor.
-Oral solution, elixir, syrup, tincture, or other solubilized forms that contain a previously
approved active ingredient and have no added inactive ingredient that is known to affect
drug absorption.

Question case scenario of sovaldi bioequivalence data

 Chapter 8: DIGOXIN TDM
Clinical Pharmacology:

Pharmacodynamic Effects
increased cardiac output
decreased pulmonary capillary wedge pressure
increased ejection fraction.

Clinical Indications

Heart failure
Atrial fibrillation

Pharmacokinetics: Absorption

Formulation F

el i xir

tablet

capsule

Pharmacokinetics: Distribution

--
:z:
...
••
07.5 -e Dt O.OllliN Y
lt

.....
::z::
·
--
"'-"

:z.
>C
0
c:J
a
•

0..0.
DIS'IUtl 8U1111'10.. P HAS'E EU MIN All" ION PHASE

...,. Qo .. .. • .,
HOURS
••

2 compartmental model:

Initial: fast, central compartment

Second: slow, peripheral tissues
The target site, the myocardium, is affected by drug concentration in the peripheral
compartment. clinical effect may not be seen until sufficient drug has accumulated at that
site, which may take several hours (8-12) after a loading dose.
Vd = 7 Llkg (IBW) [use ABW in underweight patients)
Plasma protein binding: 30%
Pharmacokinetics: Metabolism

< 20% metabolism by the liver (stepwise cleavage of the sugar moiety and lactone ring
reduction).
No significant role of Cytochrome P450 enzymes.
Digoxin metabolites have minor cardioactive effect compared to the parent drug.

Pharmacokinetics: Excretion

80 % of a digoxin dose is eliminated as unchanged drug by the kidneys.

a mixture of glomerular filtration and active tubular secretion.
Tubular secretion is mediated primarily by the P-glycoprotein transporter and is subject
to drug interaction risks.
Patients with severe renal dysfunction may encounter drug accumulation and toxicity.
Monitoring of renal function is necessary

Pharmacokinetics: Clearance Estimation

of Digoxin Clearance (Cl) Cldigoxin =

1.303 CrCl (mUmin) + Clm Clm is the

non-renal clearance
= 20 ml/min for patients with heart failure
= 40 ml/min for patients without heart failure

Therapeutic Concentration

Indication Target concentration (ng/rnL)

CHF 0.7-1.2

Atrial Fibrillation 0.5-2.0

Sampling:

Serum digoxin concentration should be obtained at approximately 6-8 hours following

the loading dose.
Levels obtained earlier may be falsely elevated due to the slow distribution phase.
Once steady state has been achieved, in 7 to 14 days after a maintenance regimen is
initiated, routine samples for digoxin monitoring should be drawn just before the next
dose is due.
 .
g
8
E
:..;.:_)

--- --.
0 t2 1 2
. hr

Dosing: Loading Dose

In CHF: Not required.

In A. Fib: to achieve a rapid attainment of target concentration.

Calculation: LD = (Vd)(C in ng/mL)/(F).

Administration: it should be given in divided dosing to decrease the occurrence of toxic

concentrations.

IV doses can be given in 2- to 4-hour intervals

oral formulations can be given in 6- to 8-hour intervals

Dosing: Loading Dose: Example 1

MS is a 47-year-old male to be initiated on intravenous digoxin for atrial fibrillation. Her weight
is 70 kg and height is 68 inches. Her CrCl is estimated to be at 95 mL/min. Calculate his digoxin
loading dose for a desired plasma concentration of 1 ng/mL.

Step 1: Vd: Vd = 7 Llkg (IBW) = 7 x 68.4 = 479 L (IBW = 68.4)

Step 2: LD: LD = (Vd)(C in ng/mL)/(F). = 479 x 1 = 479 ng (approximately 0.5 mg)
(Give 250 ng now and another 250 mg in 2-4 hours)
Dosing: Maintenance Dose
90 n 79
76 78
7S 77
74 70
7) 7S

72 74
G.2S mg dolly 71 7J
70 72
69 71
6e70i
67 09'
661!1115"
6S 67
0.12Smgd.oil)<
64 «1
6l OS
67 64
61 63
so 60 62
S9 61

------ ------ ------ -------- ------ ------

0 20 100
60
1 20 /

!....,..,.., ..._......... Ol ldNaOcs

----· ,.,.....,., c.m
..---- --.
Dosing: Maintenance Dose

2. PK Equation

Maintenance dose= (CL)(Css)('()/(F)

where CL is the clearance of digoxin, Css is the steady state concentration, '( is the dosing
interval in days and F is the bioavailability ofthe formulation.

Dosing: Maintenance Dose: Example 2

Calculate a maintenance dose (oral tablets) forMS in Example 1.

CL = 1.303 CrCI (mUmin) + CLm• Clm = 40 mL/ rnin.

OVhere Cl m is non-renal clearance and Clm = 20 rnL/ min for
patients w-ith heart failure and 40 mL/ min for patients "'-rith-
out heart failure)
- 1.303 x 95 m L/ n'lin + 40
- 163.8 n"'lL/ min

Converting to Uday = [(163.8 m.Umin)( lA40 min /day)]/ 1,000 mUL

= 235.9 Uday

Maintenance

= 337 me - 375 me , or 0.375 rn

Dosing: Maintenance Dose:

3. Based on digoxin serum concentration

A more patient-specific maintenance dose can be determined using the patient's dosing history
and the observed digoxin concentrations to derive a patient-specific drug clearance.

CL = (MD)(F)/(Css)l"[)

Maintenance dose = (CL)(Css })(/I E)

Dosing: Maintenance Dose: Example 3

Assuming MS (from Example 2) was initiated on 0.375 mgtablets daily and in 14 days a steady-
state serum digoxin concentration was obtained right before the next scheduled dose. The Css
was measured to be 2.8 ng/mL. Calculate his true CL and a new dosing regimen to attain a new
desired Css of 1.5 ng/mL.
CL = (375 mcg)(0.7)/(2.8 ng!mL) (l day)
= 93.8 L/day (Note: Her true CL is significantly
different from the estimated 229.3 L/day.)

New MD= (93.8 Llday)(l.S ng/mL)(lday)/(0.7)

= 201 mcg!day (rounded up to 250 meg
or 0.25 mg tabs daily)

PK of Digoxin in Special Populations

Population PK changes

Renal Reduced clearance and Vd. V =(226+

298
• C.CI )(Wt/70)=
Dysfunction 29.1 T CrCJ

Dose adjustment: lower digoxin loading and maintenance doses,

and extension of dosage interval.
Geriatric Renal function declines (less effective nephrons) and Vd
decreases (less skeletal muscles)
Dose adjustment: the elderly patient should be managed as
though they have recognized renal disease
Heart Failure As compared to healthy adults, the clearance of digoxin is
reduced 50% in those patients with heart failure
Hyperthyroidism Myocardial sensitivity and response to digoxin are reduced. Vd
and elimination of digoxin increase.
Dose adjustment: use of higher loading doses.
Hypothyroidism Reverse of hyperthyroidism

Drug Interactions
 pgp inhibitors: They are expected to increase digoxin exposure by more than 25%. e.g:
®
amiodarone, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem,
dronedarone, felodipine, itraconazole, lopinavir and ritonavir, quinidine, ranolazine,
ticagrelor, and verapamil.

pgp inducers: They are expected to decrease digoxin AUC by greater than 20%. e.g.
phenytoin, rifampin, St. John's wort, and tipranavir/ritonavir.

CASE 1:

A 47-year-old female, IBW 63.5 kg, is to be initiated on digoxin for atrial fibrillation. Calculate
an appropriate digoxin loading dose and maintenance dose if the patient is to be started on an
intravenous loading and oral maintenance dose using digoxin tablets. Assume her CrCl is 80
mL/min and her target Css is 1 ng/mL

Case2:

A 73-year-old male with moderate CHF is to be initiated on digoxin. Calculate an appropriate

oral regimen to target a goal of 0.8 ng/mL using digoxin tablets via his orogastric (OG) tube.
Assume his CrCl is 35 mL/min.

Self-study examples:

1. UV is a 75-year-old, 62-kg (height= 5 ft 9 in) male with atrial fibrillation. His current
serum creatinine is 1.3 mg/dL, and it has been stable since admission. Compute an
intravenous loading and maintenance digoxin dose for this patient to provide a steady-
state concentration of 1.5 ng/mL..
2. Patient UV (see problem 1) was prescribed digoxin 200 11g/d intravenously, and this dose
has been given for 2 weeks. A steady-state digoxin concentration was 2.4 ng/mL. Compute
a revised digoxin dose for this patient to provide a steady-state concentration of
1.5 ng/mL.
3. Patient UV (see problems 1 and 2) had a dosage change to digoxin 125 Jlg/d
intravenously which produced a steady-state concentration equal to 1.4 ng/mL. Compute
an oral tablet digoxin dose for this patient that will provide about the same steady-state
drug concentration as that found during intravenous therapy..
4. SD is a 35-year-old, 75-kg (height = 5 ft 7 in)) female with NYHA Class IV heart failure
secondary to viral cardiomyopathy. Her current serum creatinine is 3.7 mg/dL, and it has
been stable since admission. Compute oral digoxin loading and maintenance doses using
tablets for this patient to provide a steady-state concentration of 1 ng/mL.
 Chapter 9: Lithium TDM
Clinical Pharmacology

Pharmacodynamic Effects
competition with other cations at receptor and tissue sites,
dopamine-receptor supersensitivity blockage,
decreased stimulation of -receptor-induced adenylate cyclase, and enhanced sensitivity
to serotonin (5-HT), acetylcholine, and GABA.

Clinical Indications

mood stabilizer for bipolar disorders

Pharmacokinetics: Absorption

PK parameter

Tm ax li t hium ci trate sy rup: 15-30 min

rapi d-release li t hium carbonate: 1 -3 h
sustained-release lithium carbonate: 4-8 h

Lithium carbonate: 8.12 mmol (or 8.12 mEq) of lithium in 300 mg

Lithium citrate: 8 mmol or mEq/5 ml

Pharmacokinetics: Distribution

0
E
g
c:
1
--
Ot or distributi on phase

-e 0. 1
or elimination phase
E
Q.>
g
8
0.01
0 10 20 30 40 so
Time (h)

Multicompartment model.
Insignificant plasma protein binding.
Significant inter-individual variations (average Vd= 0.9 L/kg).

Pharmacokinetics: Elimination

Lithium is eliminated almost completely (>95%) unchanged in the urine with elimination tl/2 of
24h.
filtered freely at the glomerulus, and subsequently 60%-80% of the amount filtered is
reabsorbed(along with Na+) by the proximal tubule of the nephron.
 consistent relationship between lithium clearance and creatinine clearance with a ratio of 20%
(lithium clearance-creatinine clearance).
Monitoring of renal function is necessary

Pharmacokinetics: Clearance

Estimation of Lithium Clearance (CI)

Cliithium (L/day) = 0.288 CrCI (ml/min)

Creatinine Clearance {mllmin)

Therapeutic Concentration

Indication Target concentration

(mEq!L)*
General 0.6- 1.5

Acute mania 0.8- 1

Acute mania- No response 1- 1.2 or 1.2- 1.5

Long-term maintenance 0.6- 0.8

Long-term maintenance- No response 0.9- 1 or 1- 1.2

These therapeutic ranges are based on steady-state lithium serum concentrations obtained 12 hours
after a dose

Narrow Therapeutic Window

> 3.0:seizure. brain

damage,CV!respiratory
LITHIUM problems. death

1.5-3.0: confusion,
Pharmacology agitation,nystagmus,
hypertonia, ataxia.
Therapeutic Range
0.6-1.2 mEqll j >1.6 mEqtL j • 1.2- 1.5:NVD, hand
tremors, reduced memory
!10-1.2 mEq/L I• TOXICITY
ACUTE MANIA

I0.6-0.8 mEq/L I . NARROW MARGIN OF SAFETY

MAINTENANCE
Therapeutic Drug Monitoring
THERAPY

Sampling
 ®
When lithium serum concentration monitoring is anticipated for an individual, the patient needs
to understand that it is important to:
take their medication as instructed for 2-3 days before the blood sample is obtained,
to have the blood sample withdrawn 12 ± 0.5 h after the last dose,and
to report any discrepancies in compliance and blood sampling time to their care provider.

Therapeutic Monitoring

Signs and symptoms of bipolar disease (mania and depression)

Onset of action for lithium is 1-2 weeks,and a 4- to 6-week treatment period is required to
assess complete therapeutic response to the drug.

Before initiation: General chemistry panel,CBC,thyroid function,urinalysis, and pregnancy test.

Lithium serum level: should be measured for every patient

Upon initiation: every 2-3 days

Once a desired level is achieved: every 1-2 weeks
During maintenance therapy: every 3-6 months
Should be 12 h following a dose (even if given TID)

Initial Dosage Determination

Maintenance dose (mEq) = (CIIithium)(Css)(T)/(F)

Cllithium (L/day) = 0.288 CrCI (ml/min) 24

where Cl is the clearance of lithium (L/day), Css is the steady state concentration (mg/L),Tis the
dosing interval in days and F is the bioavailability of the formulation (100% for all Lithium
formulations).

Example 1

MJ is a 50-year-old,70-kg (height= 5 ft 10 in) male with bipolar disease. He is not currently experiencing
an episode of acute mania. His serum creatinine is 0.9 mg/dl. Compute an oral lithium dose for this
patient for maintenance therapy

Example 2

MJ is a 50-year-old,70-kg (height= 5 ft 10 in) male with bipolar disease. He is not currently experiencing
an episode of acute mania. His serum creatinine is 3.5 mg/dl. Compute an oral lithium dose for this
patient for maintenance therapy
Dosage Adjustment

Example 3

YC is a 37-year-old, 55-kg (height= 5 ft 1in) female with bipolar disease. She is currently not
experiencing an episode of acute mania and requires prophylactic treatment with lithium. Her serum
creatinine is 0.6 mg/dl. The patient is receiving 900 mg of lithium carbonate at 0800 H, 1400 H,and
2000 H,and her 12-hour pos-tdose steady-state lithium serum concentration equals 1.1mmoi/L.
Compute a new lithium dose to achieve a steady state concentration of 0.6 mmoi/L

Drug Interactions

Thiazide Na and H2 0 depl etion leads to lithium clearance decreases by

diuretics increased sodium (and so Li+) 40%-50%.
reabsorption in the proximal tubule of Loop diuretics and amiloride
the kidney as a compensatory have minimal effect on Li+
mechanism pharmacokinetics
NSAIDs NSAID-induced decrease in renal decrease lithium clearance and
blood flow via inhibition of increase lithium
prostaglandins concentrations.

ACEs and Inhibition of the elimination of lithium lithium serum concentrations

ARBs by an undefined mechanism increases by as much as
200%-300%.
Theophylline increases the lithium clearance- decrease in steady-state
creatinine clearance ratio by as lithium concentrations
much as 58%

Practice Cases

1. PG is a 67-year-old, 72-kg (height= 6ft 1in,serum creatinine= 1.2 mg/dl)male with bipolar disease
requiring maintenance therapy with oral lithium. Suggest an initial lithium carbonate dosage regimen
designed to achieve a steady-state lithium concentration equal to 0.6 mmoi/L.

2. Patient PG (see problem 1) was prescribed lithium carbonate 900 mg orally every 12 hours. The
current 12-hour post-dose steady-state lithium concentration equals 1.0 mmoi/L. Compute a new
lithium carbonate dose that will provide a steady-state concentration of 0.6 mmoi/L.

3. DU is a 21-year-old,70-kg (height= 5 ft 9 in,serum creatinine= 0.8 mg/dL) female with bipolar

disease who requires therapy with lithium. She is currently experiencing an episode of acute mania.
Suggest an initial lithium carbonate dosage regimen designed to achieve a steady-state lithium
concentration equal to 0.8 mmoi/L.

4. Patient DU (see problem 3) was prescribed lithium carbonate 600 mg orally at 0800 H, 1400 H,and
2000 H. The current 12-hour post-dose steady state lithium concentration equals 0.6 mmoi/L. Compute
a new oral lithium dose that will provide a steady-state concentration of 1mmoi/L.
Zero order reaction Cp Versus time plot after a single oral
𝑪𝟐 − 𝑪𝟏 dose
𝒔𝒍𝒐𝒑𝒆 = −𝒌 ∘=
𝒕𝟐 − 𝒕𝟏 𝑭 𝑫 𝑲𝒂
𝒀 𝒊𝒏𝒕𝒆𝒓𝒆𝒑𝒕 =
𝑨∘ 𝑽𝒅 (𝑲𝒂 − 𝒌)
𝒕𝟏 =
𝟐𝑲 ∘
𝟐
The area under the curve (AUC)
𝑨 = 𝑨 ∘ −𝑲𝒕
𝑭 . 𝑫𝒐𝒔𝒆 𝑭 . 𝑫𝒐𝒔𝒆
𝑨𝑼𝑪{𝒕=∞
𝒕=𝟎 = =
First order reaction 𝑻𝑩𝑪 𝑲 𝑽𝒅

−𝑲 𝒍𝒐𝒈 𝑪𝟐 −𝒍𝒐𝒈𝑪𝟏 The Renal and metabolic excration of

Slope = 𝟐.𝟑𝟎𝟑 = 𝒕𝟐− 𝒕𝟏 Drugs
𝒀 𝒌 = 𝒌𝒆 + 𝒌𝒎 + 𝒌𝒖
𝒍𝒏 𝟐⁄𝒀
𝟏
K= 𝑿𝟐 −𝑿𝟏 𝒌 . 𝑽 𝒅 = 𝒌𝒆 . 𝑽 𝒅 + 𝒌𝒎 . 𝑽 𝒅 + 𝒌𝒖 . 𝑽 𝒅

𝒀 𝜟𝑨𝒆
𝒍𝒐𝒈 𝟐⁄𝒀 = 𝒌𝒆 . 𝑨 = 𝒌𝒆 . 𝑽𝒅 . 𝑪𝒑𝒕 𝒎𝒊𝒅 = 𝒌𝒆 . 𝑨 ∘ . 𝒆−𝒌 𝒕𝒎𝒊𝒅
K= 𝟏
× 𝟐. 𝟑𝟎𝟑 𝜟𝒕
𝑿𝟐 −𝑿𝟏
𝜟𝑨𝒆
𝒍𝒏 = 𝒍𝒏 𝒌𝒆 . 𝑨 ∘ −𝒌 . 𝒕𝒎𝒊𝒅
First order elimination 𝜟𝒕
𝜟𝑨𝒆 𝒌 . 𝒕𝒎𝒊𝒅
𝑪𝒑 = 𝑪𝒑 ∘ 𝒆−𝒌𝒕 𝒍𝒐𝒈 = 𝒍𝒐𝒈 𝒌𝒆 . 𝑨 ∘ −
𝜟𝒕 𝟐. 𝟑𝟎𝟑
𝒌𝒕
𝒍𝒐𝒈 𝑪𝒑 = 𝒍𝒐𝒈 𝑪𝒑 ∘ − 𝑻𝑩𝑪 = 𝑹 𝒄𝒍 + 𝑴. 𝒄𝒍
𝟐. 𝟑𝟎𝟑
𝜟𝑨
𝒍𝒏 𝑪𝒑 = 𝒍𝒏 𝑪𝒑 ∘ −𝒌𝒕
𝑹𝒆𝒏𝒂𝒍 𝒄𝒍 = 𝒌𝒆 . 𝑽𝒅 = 𝜟𝒕
𝟎. 𝟔𝟗𝟑 𝑪𝒑𝒕 𝒎𝒊𝒅
𝒕𝟏 =
𝟐 𝒌 𝑻𝑩𝑪 = 𝑲. 𝑽𝒅
−𝒌𝒕
𝑨=𝑨∘𝒆 𝑲𝒆 𝑨𝒆∞ 𝑨𝒆∞
𝑹𝒆𝒏𝒂𝒍 𝒄𝒍 = 𝑻𝑩𝑪 × = 𝑻𝑩𝑪 × =
𝒌 𝑭 . 𝑫 𝑨𝑼𝑪𝒊𝒗
𝒌𝒕
𝒍𝒐𝒈 𝑨 = 𝒍𝒐𝒈 𝑨 ∘ −
𝟐. 𝟑𝟎𝟑 𝑨𝒆∞ 𝒐𝒓𝒂𝒍
𝑨𝒃𝒔𝒐𝒍𝒖𝒕𝒆 𝑭 =
𝒍𝒏 𝑨 = 𝒍𝒏 𝑨 ∘ −𝒌𝒕 𝑨𝒆∞ 𝒊𝒗

After a bolus IV administration 𝑨𝒆∞ 𝒕𝒆𝒔𝒕

𝑨𝒃𝒔𝒐𝒍𝒖𝒕𝒆 𝑭 =
𝒂𝒎𝒐𝒖𝒏𝒕 𝑨𝒆∞ 𝒓𝒆𝒇𝒆𝒓𝒂𝒏𝒄𝒆
𝒄𝒐𝒏𝒄 =
𝑽𝒐𝒍𝒖𝒎𝒆
𝑫𝒐𝒔𝒆 AUC by trapezoidal rule
𝑪𝒑 ∘=
𝑽𝒅
𝑨𝑼𝑪 = (𝟏⁄𝟐)(𝑪𝟎 + 𝑪𝟏)(𝒕𝟏 − 𝒕𝟎) + (𝟏⁄𝟐)(𝑪𝟏 + 𝑪𝟐)(𝒕𝟐 − 𝒕𝟏)
𝑪𝒑 ∘ 𝑪 𝒍𝒂𝒔𝒕
𝑨𝑼𝑪 {𝒕=∞
𝒕=𝟎 = + ……..+
𝑲 𝑲

After oral administration of the drug After oral Administration

𝑭𝑫𝑲𝒂 Absolute Bioavailability
𝑪𝒑 = (𝒆−𝒌𝒕 − 𝒆−𝒌𝒂𝒕 )
𝑽𝒅 (𝑲𝒂 − 𝒌)
𝑨𝑼𝑪𝒐𝒓𝒂𝒍
𝑭=
𝑭𝑫𝑲𝒂 −𝒌𝒕 𝑨𝑼𝑪𝒊𝒗
𝑨= (𝒆 − 𝒆−𝒌𝒂𝒕 )
𝒌𝒂 − 𝒌
𝑨𝑼𝑪𝒐𝒓𝒂𝒍 𝑫𝒐𝒔𝒆𝒊𝒗
𝑭= ×
𝒌𝒂 𝑨𝑼𝑪𝒊𝒗 𝑫𝒐𝒔𝒆𝒐𝒓𝒂𝒍
𝒍𝒏
𝒕𝒎𝒂𝒙 = 𝒌
Relative Bioavailability
𝒌𝒂 − 𝒌
 𝑨𝑼𝑪𝒄𝒂𝒑 𝑫𝒐𝒔𝒆𝒕𝒂𝒃 - 24 hr urine collection:
𝑭𝒓𝒆𝒍𝒂𝒕𝒊𝒗𝒆 = ×
𝑨𝑼𝑪𝒕𝒂𝒃 𝑫𝒐𝒔𝒆𝒄𝒂𝒑
𝑼𝒄𝒓 ×𝟐𝟒 𝒉𝒓 𝒗𝒐𝒍𝒖𝒎𝒆
𝑪𝒓𝑪𝒍 =
During constant rate iv infusion 𝑷𝒄𝒓 ×𝟔𝟎×𝟐𝟒

𝒌∘ - using Cockcroft-Gault formula

𝑪𝒑𝒔𝒔 =
𝒌 𝑽𝒅
For male
𝑳. 𝑫 = 𝑪𝒔𝒔 . 𝑽𝒅 = 𝑪𝒑 ∘ 𝑽𝒅
(𝟏𝟒𝟎 − 𝒂𝒈𝒆) × (𝒘𝒕 𝒊𝒏 𝒌𝒈)
At SS during multiple administration 𝑪𝒓𝑪𝒍 =
𝟕𝟐 × (𝑺. 𝑪𝒓 𝒊𝒏 𝒎𝒈⁄𝒅𝒍)
𝑭 . 𝑫𝒐𝒔𝒆
𝑪𝒎𝒂𝒙 =
𝑽𝒅 (𝟏 − 𝒆−𝒌𝝉 )
Wt= IBW for male

𝑪𝒎𝒊𝒏 = 𝑪𝒎𝒂𝒙 . 𝒆−𝒌𝝉 For female

𝒍𝒏 𝑪𝒎𝒊𝒏 = 𝒍𝒏 𝑪𝒎𝒂𝒙 − 𝒌𝝉 (𝟏𝟒𝟎 − 𝒂𝒈𝒆) × (𝒘𝒕 𝒊𝒏 𝒌𝒈)
𝑪𝒓𝑪𝒍 = 𝟎. 𝟖𝟓 ×
𝑭 . 𝑫𝒐𝒔𝒆 𝟕𝟐 × (𝑺𝑪𝒓 𝒊𝒏 𝒎𝒈⁄𝒅𝒍)
𝑪𝒎𝒂𝒙 − 𝑪𝒎𝒊𝒏 =
𝑽𝒅
Wt=IBW for female
At Steady state - CrCl for obese
Infusion rate = elimination rate 𝒘𝒕 (𝒌𝒈)
𝑩𝑴𝑰 = 𝒊𝒇 ≥ 𝟑𝟎 (𝒐𝒃𝒆𝒔𝒆)
𝑯𝒕 (𝒎𝟐 )
𝑭 . 𝑫𝒐𝒔𝒆 𝑨𝑼𝑪
𝑪𝒂𝒗𝒂𝒓𝒂𝒈𝒆 = =
𝑲 . 𝑽𝒅 . 𝝉 𝝉 ABW/IBW ≥I.3

𝑹𝒂𝒄𝒄𝒖𝒎 = 𝟏⁄𝒌 . 𝝉 [(𝟏𝟒𝟎 − 𝒂𝒈𝒆) 𝒙 𝑨𝒋𝑩𝑾]

𝑪𝒓𝑪𝒍𝒎𝒂𝒍𝒆 =
𝑺𝑪𝒓 𝒙 𝟕𝟐
𝒕𝒔𝒔 = 𝟓 𝒕𝟏⁄
𝟐 [(𝟏𝟒𝟎 − 𝒂𝒈𝒆) 𝒙 𝑨𝒋𝑩𝑾]
𝑪𝒓𝑪𝒍𝒇𝒆𝒎𝒂𝒍𝒆 = 𝟎. 𝟖𝟓 ×
𝑪𝒔𝒔 − 𝑪𝒑 −𝑲𝒕 𝑺𝑪𝒓 𝒙 𝟕𝟐
𝒕𝟏⁄ 𝒐𝒇 𝒑𝒂𝒕𝒊𝒆𝒏𝒕 = 𝒍𝒐𝒈 ( )=
𝟐 𝑪𝒔𝒔 𝟐. 𝟑𝟎𝟑 𝑨𝒋𝑩𝑾 = 𝑰𝑩𝑾 + 𝟎. 𝟒(𝑨𝑩𝑾 − 𝑰𝑩𝑾)
In patients with Renal dysfunction Ideal Body weight
𝑫 𝒇𝒂𝒊𝒍𝒖𝒓𝒆 = 𝑫 𝒏𝒐𝒓𝒎𝒂𝒍 × [𝒇 (𝒌𝑭 − 𝟏) + 𝟏]
For male
𝒕𝟏⁄
𝟐 𝒏𝒐𝒓𝒎𝒂𝒍 𝑰𝑩𝑾 = 𝟓𝟎 + (𝟐. 𝟑𝒙 𝒉𝒆𝒊𝒈𝒉𝒕 𝒊𝒏 𝒊𝒏𝒄𝒉𝒆𝒔 𝒎𝒐𝒓𝒆 𝒕𝒉𝒂𝒏 𝟓 𝒇𝒐𝒐𝒕)
𝒕𝟏⁄ =
𝟐 𝒇𝒂𝒊𝒍𝒖𝒓𝒆 [𝒇 (𝒌𝑭 − 𝟏) + 𝟏]

𝑫𝒇𝒂𝒊𝒍 𝑫𝒏𝒐𝒓𝒎𝒂𝒍
For female
=
𝑪𝒍𝒇𝒂𝒊𝒍 𝑪𝒍𝑵𝒐𝒓𝒎𝒂𝒊𝒍 𝑰𝑩𝑾 = 𝟒𝟓 + (𝟐. 𝟑𝒙 𝒉𝒆𝒊𝒈𝒉𝒕 𝒊𝒏 𝒊𝒏𝒄𝒉𝒆𝒔 𝒎𝒐𝒓𝒆 𝒕𝒉𝒂𝒏 𝟓 𝒇𝒐𝒐𝒕)

𝑫𝒏𝒐𝒓𝒎𝒂𝒍 × 𝒕𝟏⁄
𝟐𝒏𝒐𝒓𝒎𝒂𝒍
= 𝑫𝒇𝒂𝒊𝒍 × 𝒕𝟏⁄
𝟐𝒇𝒂𝒊𝒍 Crcl for pediatric
𝒕𝒐𝒕𝒂𝒍 𝒂𝒎𝒐𝒖𝒏𝒕 𝒆𝒙𝒄𝒓𝒆𝒕𝒆𝒅 Schwartz equation:
𝒇=
𝑫𝒐𝒔𝒆
𝒍𝒆𝒏𝒈𝒕𝒉 (𝒄𝒎) × 𝒌
𝑲𝒆 𝑹𝒄𝒍 𝑹𝒄𝒍 𝑨𝒆∞ 𝑪𝒓𝑪𝒍 =
𝒇= = = = 𝑺𝑪𝒓
𝑲 𝑻𝑩𝑪 𝑲 . 𝑽𝒅 𝑭. 𝑫
𝟎.𝟒𝟓 𝒇𝒓𝒐𝒎 𝟏𝒕𝒐 𝟓𝟐 𝒘𝒆𝒆𝒌𝒔
𝟎.𝟓𝟓 𝒇𝒓𝒐𝒎 𝟏 𝒕𝒐 𝟏𝟑 𝒚𝒆𝒂𝒓𝒔
𝒌 =𝟎.𝟓𝟓 𝒇𝒓𝒐𝒎 𝟏𝟑 𝒕𝒐 𝟏𝟖 𝒚𝒆𝒂𝒓𝒔 𝑭𝒆𝒎𝒂𝒍𝒆
𝟎.𝟕 𝒇𝒓𝒐𝒎 𝟏𝟑 𝒕𝒐 𝟏𝟖 𝒚𝒆𝒂𝒓𝒔 𝒎𝒂𝒍𝒆
Where;
Dose adjustment in pediatric
𝑪𝒓𝑪𝒍 𝒐𝒇 𝒇𝒂𝒊𝒍𝒖𝒓𝒆 𝒄𝒂𝒔𝒆 𝑮𝑭𝑹𝑭𝒂𝒊𝒍𝒖𝒓𝒆
𝑲𝑭 = = BSA = 0.007184 × Wt 0.425 × Ht 0.725
𝑪𝒓𝑪𝒍 𝒐𝒇 𝒏𝒐𝒓𝒎𝒂𝒍 𝒄𝒂𝒔𝒆 𝑮𝑭𝑹𝒏𝒐𝒓𝒎𝒂𝒍

Measurement of Creatinine clearance The Wagner Method

𝑲 = 𝒃 (𝑪𝒍𝒄𝒓) + 𝒂 Vmax Adult: 7 mg/kg/day

Dialysis clearance 7-16 years: 9 mg/kg/day

𝑸 × (𝑪𝒂 − 𝑪𝒗 ) ½-6 years: 12 mg/kg/day

𝑪𝒍𝑫 =
𝑪𝒂
Km Adult: 4 mg/L
𝑭×𝑫∘
𝑪∞
𝒂𝒗 = 7-16 years :6mg/L
(𝑪𝒍𝒕 + 𝑪𝒍𝑫 )𝝉
½-6 years: 6 mg/L
• Phenytoin Vd 0.7 L/kg*
Administration rate on steady state 𝑽𝒎𝒂𝒙 × 𝑪𝒑𝒔𝒔
𝑴𝑫 =
𝑺(𝑲𝒎 + 𝑪𝒑𝒔𝒔 )
Michaels- Menten
𝑪𝒑𝒔𝒔 × 𝑽𝒅
𝑳𝑫 =
Rate in = rate out 𝑺
𝜟𝑨 𝑽𝒎𝒂𝒙 𝑪𝒑𝒔𝒔 for loading dose in obese
𝑹= =
𝜟𝒕 𝒌𝒎 + 𝑪𝒑𝒔𝒔
𝑨𝒅𝒋𝑩𝑾 = 𝑰𝑩𝑾 + 𝟏. 𝟑𝟑 (𝑨𝑩𝑾– 𝑰𝑩𝑾)
𝑽𝒎𝒂𝒙 × 𝑺
𝑽=
𝑲𝒎 + 𝑺 When one steady state serum level available
at steady state of multiple oral administration 𝒌𝒎
𝑽𝒎𝒂𝒙 = 𝑫𝒂𝒊𝒍𝒚 𝒅𝒐𝒔𝒆 (𝒎𝒈⁄𝒅𝒂𝒚) × (𝟏 + )
𝑪𝒔𝒔
𝑽𝒎𝒂𝒙 𝑭 .𝑫
𝑹= × 𝑪𝒑𝒔𝒔 = 𝑴𝑫 𝑴𝑫
𝒌𝒎 + 𝑪𝒑𝒔𝒔 𝝉 (𝒐𝒍𝒅) = (𝒏𝒆𝒘)
𝑽𝒎𝒂𝒙 𝑽𝒎𝒂𝒙
𝑽𝒎𝒂𝒙
𝑻𝑩𝑪 =
𝒌𝒎 + 𝑪𝒑𝒔𝒔 Linear transformation method
𝟎. 𝟔𝟗𝟑 × 𝑽𝒅 𝑽𝒎𝒂𝒙
𝒕𝟏⁄ = 𝒊𝒏𝒕𝒆𝒓𝒄𝒆𝒑𝒕 =
𝟐 𝑻𝑩𝑪 𝑺. 𝑭
𝟎. 𝟔𝟗𝟑 × 𝑽𝒅 𝑺𝒍𝒐𝒑𝒆 = −𝒌𝒎
𝒕𝟏⁄ = × (𝒌𝒎 + 𝑪𝒑𝒔𝒔 )
𝟐 𝑽𝒎

Vd=0.7/kg, using ABW Formulation S

• for obese Phenytoin Na+ (caps, IV) 0.92
𝑽𝒅 = 𝟎. 𝟕 𝑳/𝑲𝒈[𝑰𝑩𝑾 + 𝟏. 𝟑𝟑(𝑻𝑩𝑾 − 𝑰𝑩𝑾) Phenytoin Acid (tabs, susp.) 1.0
𝑪𝒐𝒃𝒔𝒆𝒓𝒗𝒆𝒅
𝑪𝒏𝒐𝒓𝒎𝒂𝒍 =
[(𝑿. 𝒂𝒍𝒃𝒖𝒎𝒊𝒏) + 𝟎. 𝟏]
X Population 𝑫 𝑫⁄𝝉 𝑽𝒎𝒂𝒙
= −𝒌𝒎 +
𝝉 𝑪𝒑𝒔𝒔 𝑺. 𝑭
0.2 Serum albumin ≤ 3 g/dl
0.1 ESRD (CrCl < 15 ml/min), dialysis

Initial dosage determination for phenytoin

Parameter Estimate (not including elderly>60 years) • Aminoglycosides
𝑫𝒐𝒔𝒆
𝑲 ∘=
𝒕`
After first dose Gentamicin/ 20-30 <1
Tobramycin
𝑲𝒐
𝑪𝒑 = (𝟏 − 𝒆−𝒌𝒕 ′) Amikacin 55-60 <4
𝑲𝑽𝒅
At steady state

𝑪𝒎𝒊𝒏 = 𝑪𝒎𝒂𝒙 𝒆−𝒌(𝝉−𝒕`) • Vancomycin

𝒌 ∘ (𝟏 − 𝒆−𝒌𝒕`) 𝑽𝒅 = 𝟎. 𝟕 𝑳⁄𝒌𝒈(𝑨𝑩𝑾)
𝑪𝒎𝒂𝒙 =
𝒌. 𝑽𝒅 (𝟏 − 𝒆−𝒌𝝉 ) 𝒌 = 𝟎. 𝟎𝟎𝟎𝟖𝟑 [𝑪𝒍𝑪𝒓] + 𝟎. 𝟎𝟎𝟒𝟒
𝑪
𝒍𝒏 𝒎𝒂𝒙
𝑪𝒎𝒊𝒏
𝒌= Clcr use IBW if IBW<ABW
𝝉 − 𝒕`
use ABW if ABM<IBW
𝑳. 𝑫 = 𝑪𝒔𝒔 𝒎𝒂𝒙 . 𝑽𝒅 use AjBW if obese
Volume of distribution (Vd) ~ 0.26 L/Kg
Indication Goal Vancomycin level*

ABW/IBW Suggested Weight

Peak Trough
0.9 - < 1.3 ABW
UTI, Skin infection 25-40 10-15
> 1.3 Adj BW**

> 0.75 - < 0.9 IBW*

HCAP, endocarditis 25-40 15-20

< 0.75 1.13 ABW meninigitis

Dose by level
𝑪
𝒍𝒏 𝟏
𝑪𝟐
𝒌= 𝜟𝒕
AG therapeutic range

K = 0.00293 (Clcr) + 0.014 𝑪𝟏 = 𝑪𝒑𝒆𝒂𝒌 × 𝒆(−𝒌×𝒕𝟐)

(−𝒌×𝒕𝟑 )
𝑪𝒕𝒓𝒐𝒖𝒈𝒉 = 𝑪𝟐 × 𝒆𝒆
Indication Goal Peak level* Goal Trough level**
(mg/L)

Gent/Tobra Amikacin Gent/Tobra Amikacin

LD=20-30 mg/kg recommend for severe infection
UTI, 3-5 12-15 < 2 (0.5-1) < 5 (1-4)
LD=Cmax Vd recommend for other infection types
Endocarditis

Bacteremia 5-7 20-25 < 2(0.5-1) < 5 (1-4)

Pneumonia 8-12 28-30 < 2(0.5-1) < 5 (1-4)

(CAP)
𝟎. 𝟔𝟗𝟑
𝒕𝟏 =
𝟐 𝒌

Clcr use IBW if IBW<ABW

use ABW if ABM<IBW
use AjBW if obese

AG Peak level (mg/L) Trough level

(8-10x MIC) (mg/L)
 Clinical Pharmacokinetics

For
Fourth Level (Pharm D Program)
2024-2025
By:
Clinical Pharmacy Department
Department of Clinical Pharmacy

College Of Pharmacy

KFS University
 Clinical pharmacokinetics Fourth Year

Syllabus
Topic Page
number

1 Revision 3

2 Dose adjustment in renal and hepatic disease 6

3 Phenytoin pharmacokinetics 10

5 Digoxin pharmacokinetics 15

6 Lithium pharmacokinetics 18

7 Aminoglycoside pharmacokinetics 23

8 Vancomycin pharmacokinetics 27

9 Bioavailability 31

2|Page
Clinical pharmacokinetics Fourth Year

Lab 1

1. Two new antibiotics are marketed by a pharmaceutical manufacture.

Reading the package insert, you find the following information:

What type of pharmacokinetics does each of these drugs follow?

3|Page
Clinical pharmacokinetics Fourth Year

A patient with liver failure and a patient with heart failure need to be treated
with a new antiarrhythmic drug. You find a research study that contains the
following information for Stopa beat in patients similar to the ones you need
to treat: • Normal subjects: clearance = 45 L/h, volume of distribution = 175
L • Liver failure: clearance = 15 L/h, volume of distribution = 300 L • Heart
failure: clearance = 30 L/h, volume of distribution = 100 L

Recommend an intravenous loading dose (LD) and continuous intravenous

infusion maintenance dose (MD) to achieve a steady state concentration of
10 mg/L for your two patients based on these data and estimate the time it
will take to achieve steady-state conditions.

4|Page
Clinical pharmacokinetics Fourth Year

After the first dose of gentamicin is given to a patient with renal failure, the
following serum concentrations are obtained:

Compute the half-life and the elimination rate constant for this patient

5|Page
Clinical pharmacokinetics Fourth Year

Lab 2

Case 1: A 24-hour urine was collected for a 60 kg woman with intra-

abdominal infection because of complicated appendicitis. The following
results are obtained • SCr after 12 hours = 88.4 micromol/L • UCr in 24
hours = 4862 micromole/L • V = 1 L/day Calculate creatinine clearance The
physician wants to start her on meropenem and asks for your
recommendations regarding dose adjustment.

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Clinical pharmacokinetics Fourth Year

Case 2: A 66-year-old, 120-kg, 5-ft 2-in-tall female has a serum creatinine

equal to 3.1 mg/dL. Compute an estimated creatinine clearance for this
patient.
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Case 3 : A 51-year-old, 54-kg, 5-ft 4-in female with worsening renal

function needs to have her renal function assessed for drug dosage
adjustment. Yesterday at 0800 H, her serum creatinine was 1.3 mg/dL.
Today at 0800 H, her serum creatinine was 2.1 mg/dL. Compute her
estimated creatinine clearance.
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7|Page
Clinical pharmacokinetics Fourth Year

Case 4: A 62-year-old, 65-kg male with hepatic cirrhosis (total bilirubin =

2.6 mg/dL, serum albumin = 2.5 mg/dL, prothrombin time prolonged over
normal by 8 seconds, slight amount of ascitic fluid, no hepatic
encephalopathy) and severe chronic obstructive pulmonary disease needs to
have an initial theophylline dose computed. The patient is not a tobacco
smoker and does not have heart failure. Compute the patient’s Child-Pugh
score, estimated theophylline clearance, and theophylline dose to achieve a
steady-state concentration

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8|Page
Clinical pharmacokinetics Fourth Year

Case 5: A 62-year-old, 65-kg male with hepatic cirrhosis (total bilirubin =

2.6 mg/dL, serum albumin = 2.5 mg/dL, prothrombin time prolonged over
normal by 8 seconds, slight amount of ascitic fluid, no hepatic
encephalopathy) and severe chronic obstructive pulmonary disease. The
patient is not a tobacco smoker and does not have heart failure. Compute the
patient’s Child-Pugh score, patient medical history includes cystic fibrosis
for which he takes tezacaftor/ivacaftor . What is your recommendation for
dose adjustment of tezacaftor/ ivacaftor considering patient’s hepatic
impairment? You are provided drug monograph as follows

9|Page
Clinical pharmacokinetics Fourth Year

Lab 3

Case 1 LM is an epileptic patient being treated with phenytoin. He has

hypoalbuminemia (albumin = 2.2 g/dL) and poor renal function (creatinine
clearance = 10 mL/min). His total phenytoin concentration is 7.5 μg/mL. I.
Compute an estimated normalized phenytoin concentration for this patient.
II. Give clinical recommendation regarding LM phenytoin concentration
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Clinical pharmacokinetics Fourth Year

Case 2 PM is an epileptic patient being treated with phenytoin and valproic

acid. He has a normal albumin concentration (albumin = 4.2 g/dL) and
normal renal function (creatinine clearance = 90 mL/min). His steady-state
total phenytoin and valproic acid concentrations are 7.5 μg/mL and 100
μg/mL, respectively. 1.Compute an estimated unbound phenytoin
concentration for this patient. 2.Give clinical recommendation regarding PM
phenytoin concentration
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Clinical pharmacokinetics Fourth Year

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Clinical pharmacokinetics Fourth Year

Case 4 UO is a 10-year-old, 40-kg male with simple partial seizures who

requires therapy with intravenous fosphenytoin. He has normal liver and
renal function. Suggest an initial fosphenytoin dosage regimen designed to
achieve a steady-state phenytoin concentration equal to 12 μg/mL
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Clinical pharmacokinetics Fourth Year

GF is a 35-year-old, 55-kg female with tonic-clonicseizures who requires

therapy with oral phenytoin. She has normal liver and renal function. The
patient was prescribed 300 mg/d of extended phenytoin sodium capsules for
1 month, and the steady-state phenytoin total concentration equals 10.7
μg/mL.The patient is assessed to be compliant with her dosage regimen.
•Suggest an initial phenytoin dosage regimen designed to achieve a steady-
state phenytoin concentration within the middle of the therapeutic range

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Clinical pharmacokinetics Fourth Year

TD is a 50-year-old, 75-kg (height = 5 ft 10 in) male with simple partial

seizures who requires therapy with oral phenytoin. He has normal liver and
renal function. The patient was prescribed 400 mg/d of extended phenytoin
sodium capsules for 1 month, and the steady-state phenytoin total
concentration equals 6.2 μg/mL.The dosage was increased to 500 mg/d of
extended phenytoin sodium capsules for another month, the steady state
phenytoin total concentration equals 22.0 μg/mL, and the patient has some
lateral-gaze nystagmus. The patient is assessed to be compliant with his
dosage regimen. •Suggest a new phenytoin dosage regimen designed to
achieve a steady- state phenytoin concentration within the therapeutic range.
Use Ludden method to estimate Vmax and Km.

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Clinical pharmacokinetics Fourth Year

Lab 5

Case 1: UV is a 75-year-old, 62-kg (height = 5 ft 9 in) male with atrial

fibrillation. His current serum creatinine is 1.3 mg/dL, and it has been stable
since admission. Compute an intravenous loading and maintenance digoxin
dose for this patient to provide a steady-state concentration of 1.5 ng/mL or
digoxin total body store equal to 15 μg/kg, compare your results with ranges
provided in the monograph. You are also given the available strengths.

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Clinical pharmacokinetics Fourth Year

Case 2 SD is a 35-year-old, 75-kg (height = 5 ft 7 in) female with NYHA

Class IV heart failure secondary to viral cardiomyopathy. Her current serum
creatinine is 3.7 mg/dL, and it has been stable since admission. Compute
oral digoxin loading and maintenance doses using tablets for this patient to
provide a steady-state concentration of 1 ng/mL. Compare your results with
ranges provided in the monograph. You are also given the available
strengths section from Digoxin monograph.

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Clinical pharmacokinetics Fourth Year

1. UV is a 75-year-old, 62-kg (height = 5 ft 9 in) male with atrial fibrillation.

His current serum creatinine is 1.3 mg/dL, and it has been stable since
admission. Compute an intravenous loading and maintenance digoxin dose
for this patient to provide a steady-state concentration of 1.5 ng/mL or
digoxin total body store equal to 15 μg/kg. Compare your results with ranges
provided in the monograph. You are also given the available strengths.

2. Patient UV was prescribed digoxin 200 μg/d intravenously, and this dose
has been given for 2 weeks. A steady-state digoxin concentration was 2.4
ng/mL. Compute a revised digoxin dose for this patient to provide a steady-
state concentration of 1.5 ng/mL

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Clinical pharmacokinetics Fourth Year

Lab 6

1. Ahmed is a 67-year-old, 72-kg (height = 6 ft 1 in, serum creatinine =

1.2 mg/dL) male with bipolar disease requiring maintenance therapy
with oral lithium. Suggest an initial lithium carbonate dosage regimen
designed to achieve a steady-state lithium concentration equal to 0.6
mmol/L

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Clinical pharmacokinetics Fourth Year

Ali was prescribed lithium carbonate 900 mg orally every 8 hours. The
current 12-hour post dose steady-state lithium concentration equals 1.0
mmol/L. Compute a new lithium carbonate dose that will provide a
steady- state concentration of 0.6 mmol/L.

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Clinical pharmacokinetics Fourth Year

LK is a 47-year-old, 65-kg (height = 5 ft 5 in) female with bipolar

disease. She is not currently experiencing an episode of acute mania. Her
serum creatinine is 0.9 mg/dL. Compute an oral lithium dose for this
patient during maintenance therapy using the Cooper nomogram

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Clinical pharmacokinetics Fourth Year

HG is a 32-year-old, 58-kg (height = 5 ft 1 in) female with bipolar

disease. She is not currently experiencing an episode of acute mania. Her
serum creatinine is 0.9 mg/dL. A single test dose of lithium (1200 mg)
was given to the patient, and lithium concentrations were measured as 0.6
mmol/L and 0.3 mmol/L at 12 hours and 36 hours, respectively, after the
drug was given. Compute an oral lithium dose for this patient which will
produce a steady-state serum concentration of 0.8 mmol/L using the
Perry Method.

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Clinical pharmacokinetics Fourth Year

Lab 7

JM is a 50-year-old, 70-kg (height = 5 ft 10 in) male with gram-negative

pneumonia. His current serum creatinine is 3.5 mg/dL, and it has been
stable over the last 5 days since admission. Compute a gentamicin dose
for this patient using conventional dosing

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Clinical pharmacokinetics Fourth Year

JM is a 20-year-old, 76-kg (height = 5 ft 8 in) male with a gram-negative

pneumonia. His current serum creatinine is 1.1 mg/dL and is stable.
Compute a tobramycin dose for this patient using extended-interval
dosing

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Clinical pharmacokinetics Fourth Year

JM is a 50-year-old, 70-kg (height = 5 ft 10 in) male with gram-negative

pneumonia. His current serum creatinine is 0.9 mg/dL, and it has been
stable over the last 5 days since admission. Compute a gentamicin dose
for this patient using conventional dosing

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Clinical pharmacokinetics Fourth Year

JM is a 50-year-old, 70-kg (height = 5 ft 10 in) male with gram- negative

pneumonia. His current serum creatinine is 0.9 mg/dL, and it has been
stable over the last 5 days since admission. Compute initial dose and
dosage interval using extended interval method A gentamicin serum
concentration measured 10 hours after the dose equals 3 μg/mL.

1. Determine dosage interval using serum concentration monitoring

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Clinical pharmacokinetics Fourth Year

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Clinical pharmacokinetics Fourth Year

Lab 8

KI is a 75-year-old, 62-kg male with S. epidermidis sepsis. His current

serum creatinine is 1.3 mg/dL, and it has been stable since admission.
Compute a vancomycin dose for this patient to provide a steady-state
peak concentration of 40 μg/mL and a steady-state trough concentration
of 15 μg/mL.

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Clinical pharmacokinetics Fourth Year

Patient KI was prescribed vancomycin 1000 mg every 36 hours. Steady-

state vancomycin concentrations were obtained before and after the
fourth dose, and the peak concentration (obtained ½ hour after a 1-hour
infusion of vancomycin) was 34 μg/mL while the trough concentration
(obtained immediately before dosage administration) was 2.5 μg/mL.

Compute a revised vancomycin dose for this patient to provide a steady-

state peak concentration of 48 μg/mL and a steady-state trough
concentration of 17 μg/mL

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Clinical pharmacokinetics Fourth Year

LK is a 55-year-old, 140-kg (5 ft 8 in) male with an MRSA wound

infection (MIC = 0.5 μg/mL). His current serum creatinine is 0.9 mg/dL,
and it has been stable since admission. Compute a vancomycin dose for
this patient to provide a steady state peak concentration of 45 μg/mL and
a steady-state trough concentration of 20 μg/mL.

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Clinical pharmacokinetics Fourth Year

GA is a 55-year-old, 78-kg (6 ft 1 in) male with an MRSA endocarditis

(MIC = 1 μg/mL). His current serum creatinine is 1.5 mg/dL, and it has
been stable over the last 3 days since admission. A vancomycin dose of
1000 mg every 18 hours was prescribed and expected to achieve an
AUC24/MIC > 400. After the third dose, the steady-state trough
concentration equaled 7 μg/mL. Using the estimated AUC24 ratio
method, calculate the AUC24/MIC ratio for the patient and compute a
new vancomycin dose that would provide an AUC24/MIC > 400.

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Clinical pharmacokinetics Fourth Year

Lab 9

The previous table represents plasma concentration after different

formulation of ofloxacin antibiotic to a subject in random study.

a-Which of the oral product would be preferred as reference for relative

bioequivalence study?

b-Which of the oral drug is absorbed more rapidly and why?

c-What is the absolute bioavailability of tablet form?

d-What is the relative bioavailability of oral tablet to oral capsule?

e-Calculate the Vd , K , t1/2, clearance of this drug?

f-If the minimum effective concentration for this drug is about 12.5
mg/L. what will be the approximate duration of action in the four
formulations?

g- Can we calculate absorption rate constant of the three oral forms and
how? without applying the residual method?

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Clinical pharmacokinetics Fourth Year

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Clinical pharmacokinetics Fourth Year

Three drugs of the same active constituent -but in different

pharmaceutical formsgive the following AUC Under different doses:
Drug A ( 80 mg IV single dose) gives AUC 20 mg.hr/L Drug B (200 mg
oral solution single dose) gives AUC 45 mg.hr/L Drug C (400 mg oral
capsule single dose) gives AUC 60 mg.hr/L

a- calculate the absolute bioavailability for drug B?

b- calculate the relative bioavailability for drug C in relation to drug B?
c- calculate the absolute bioavailability for drugs

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