Multiple Dosage Regimens

Dr. Muhammad Usman

Assistant Professor
IPS, UVAS, Lahore
[email protected]
 Introduction
• After single-dose drug administration, the plasma drug level
rises above and then falls below the minimum effective
concentration (MEC), resulting in a decline in therapeutic
effect.
• To treat chronic disease, multiple dosage or IV infusion
regimens are used to maintain the plasma drug levels within
the narrow limits of the therapeutic window (e.g, plasma drug
concentrations above the MEC but below the minimum toxic
concentration or MTC) to achieve optimal clinical
effectiveness e.g antibacterials, cardiotonics, anticonvulsants,
hypoglycemics, antihypertensives, hormones, and other

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 Introduction
• Ideally, a dosage regimen is established for each drug to
provide the correct plasma level without excessive fluctuation
and drug accumulation outside the therapeutic window
• In calculating a multiple-dose regimen, the desired or target
plasma drug concentration must be related to a therapeutic
response, and the multiple-dose regimen must be designed to
produce plasma concentrations within the therapeutic
window
There are two main parameters that can be adjusted in
developing a dosage regimen:
1. The size of the drug dose and
2. The frequency of drug administration (the time interval
between doses “τ”).
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 Introduction
• To calculate a multiple-dose regimen for a patient
or patients, pharmacokinetic parameters are first
obtained from the plasma level–time curve
generated by single-dose drug studies.
• With these pharmacokinetic parameters and
knowledge of the size of the dose and dosage
interval (t), the complete plasma level–time curve
or the plasma level may be predicted at any time
after the beginning of the dosage regimen.

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 Drug Accumulation
Principle of superposition:
• The principle of superposition assumes that early
doses of drug do not affect the pharmacokinetics
of subsequent doses.
• Therefore, the blood levels after the second,
third, or nth dose will overlay or superimpose the
blood level attained after the (n-1)th dose.
In addition, the AUC(0-t) for the first dose is
equal to the steady-state area between doses.

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 Drug Accumulation
The principle of superposition allows the
pharmacokineticist to project the plasma drug
concentration–time curve of a drug after multiple
consecutive doses based on the plasma drug
concentration–time curve obtained after a single dose.
The basic assumptions are
1. The drug is eliminated by first-order kinetics.
2. The pharmacokinetics of the drug after a single dose
(first dose) are not altered after taking multiple doses
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 Drug Accumulation
There are situations, however, in which the superposition
principle does not apply. In these cases, the
pharmacokinetics of the drug change after multiple dosing
due to various factors, including
• Changing pathophysiology in the patient,
• Saturation of a drug carrier system,
• Enzyme induction, and
• Enzyme inhibition.
Drugs that follow nonlinear pharmacokinetics generally do
not have predictable plasma drug concentrations after
multiple doses using the superposition principle.
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 Drug Accumulation
• If the drug is administered at a fixed dose and a fixed
dosage interval, the amount of drug in the body will
increase and then plateau to a mean plasma level higher
than the peak Cp obtained from the initial dose.
• When the second dose is given after a time interval
shorter than the time required to “completely”
eliminate the previous dose, drug accumulation will
occur in the body.
• However, if the second dose is given after a time interval
longer than the time required to eliminate the previous
dose, drug will not accumulate.
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 Drug Accumulation
• As repetitive equal doses are given at a constant
frequency, the plasma level–time curve plateaus and
a steady state is obtained. At steady state, the
plasma drug levels fluctuate between Cmax∞ and Cmin
∞.
• Once the steady state is obtained, Cmax∞ and Cmin ∞
are constant and remain unchanged from dose to
dose.
• The Cmax∞ is importat in determining the drug safety
and should remain below MTC. It is also a good
indicator of drug accumulation
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 Drug Accumulation (R)
• If Cmax∞ = (Cn-1) max No Accumulation
• If Cmax∞ > (Cn-1) max Accumulation

Drug accumulation (R) depends on the elimination rate constant

and the dosing interval and is independent of the dose

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 Drug Accumulation
• The time required to reach steady state is dependent on the
elimination half-life of the drug and is independent of the size
of the dose, the dosing interval, and the number of doses.
• Therefore, if the dose or dose interval is altered, the time
required to achieve steady state is same.

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• An average steady-state plasma drug
concentration is obtained by dividing the area
under the curve (AUC) for a dosing period by
the dosing interval “τ”, at steady state

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 Repetitive IV Injections
• The maximum amount of drug in the body following a single
rapid IV injection is equal to the dose of the drug.
• For a one-compartment open model, the drug will be
eliminated according to first-order kinetics
• The amount of drug remaining in the body after dosage
interval “τ” can be determined with

• The fraction ( f ) of the dose remaining in the body is

related to the elimination constant (k) and the dosage
interval (τ) as follows

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 Example
• A patient receives 1000 mg every 6 hours by repetitive IV
injection of an antibiotic with an elimination half-life of 3
hours. Assume the drug is distributed according to a one-
compartment model and the volume of distribution is 20 L.
a) Find the maximum and minimum amounts of
drug in the body (Dmax, Dmin, Dav)
b) Determine the maximum and minimum plasma
concentrations of the drug (Cmax, Cmin, Cav).
𝒇 = 𝒆−𝒌𝝉

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Example

D0 = 1000 mg

Dmax = 1333 mg

Dmin = 333 mg

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 ∞ 𝐷0
• 𝐷𝑚𝑎𝑥 =
1−𝑓
∞ 1000 1000
• 𝐷𝑚𝑎𝑥 = = = 1333 mg
1−0.25 0.75
∞ ∞
• 𝐷𝑚𝑖𝑛 = 𝐷𝑚𝑎𝑥 − 𝐷0
∞
• 𝐷𝑚𝑖𝑛 = 1333 − 1000 = 333 𝑚𝑔
∞ 𝐹𝐷0
• 𝐷𝑎𝑣 =
𝑘τ
∞ 𝐹𝐷0 1.44 𝑡1/2
• 𝐷𝑎𝑣 =
τ
∞ = 1 1000 1.44 (3)
• 𝐷𝑎𝑣 = 720 𝑚𝑔
6

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• To find Cmax, Cmin and Cav
∞ 1333
𝐶𝑚𝑎𝑥 = = 66.65 mg/L
20

∞ 333
𝐶𝑚𝑖𝑛 = = 16.65 mg/L
20

∞ = 720
𝐶𝑎𝑣 = 36 mg/L
20

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A more direct approach to find Cmax, Cmin and Cav

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 Example
• A patient receives 500 mg every 12 hours by repetitive
IV injection of an antibiotic with an elimination half-life
of 4 hours. Assume the drug is distributed according to
a one-compartment model and the volume of
distribution is 30 L.
a) Find the maximum, minimum and average amounts of
drug in the body (Dmax, Dmin, Dav)
b) Determine the maximum, minimum and average
plasma concentrations of the drug (Cmax, Cmin, Cav).

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 ∞
• The 𝐶𝑎𝑣 is often the target drug concentration for
optimal therapeutic effect and gives an
indication as to how long this plasma drug
concentration is maintained during the dosing
interval (between doses).
∞
• The Cav is dependent on AUC and dose interval
𝑡2
∞ =
[𝐴𝑈𝐶] 𝑡1
𝐶𝑎𝑣
τ
𝑡2
𝐹𝐷0 𝐹𝐷0
𝐴𝑈𝐶𝑡1 = =
𝐶𝐿 𝑘𝑉𝑑

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• It is sometimes desirable to know the plasma drug
concentration at any time after the administration of n doses
of drug. The general expression for calculating this plasma
drug concentration is;
• Before reaching steady state

• Where: n is the number of doses and t is time after last dose

By considering the last example. Calculate the plasma
concentration at 3 hours after administration of 2nd dose

= 31.3 mg/L

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• After reaching steady state:
The factor 𝑒 −𝑛𝑘τ approaches to zero.

By considering the last example. Calculate the steady state

plasma concentration at 3 hours after administration of last dose

= 33.3 mg/L

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A patient receives 1000 mg every 6 hours by repetitive IV
injection of an antibiotic with an elimination half-life of 3 hours.
Assume the drug is distributed according to a one-
compartment model and the volume of distribution is 20 L.

1. Calculate the plasma concentration at 4 hours after

administration of 3rd dose

2. Calculate the steady state plasma concentration at 5 hours

after administration of last dose

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 Problems with missed dose
A cephalosporin (k = 0.2 h-1, VD = 10 L) was
administered by IV multiple dosing; 100 mg was
injected every 6 hours for 6 doses. What was the
plasma drug concentration 4 hours after the
sixth dose (ie, 40 hours later) if
(a) the fifth dose was omitted,
(b) the sixth dose was omitted,
(c) the fourth dose was omitted?

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Loading 1st 2nd 3rd 4th 5th 6th 7th
dose dose dose dose dose dose dose dose

0 hour 6 hour 12 hour 18 hour 24 hour 30 hour 36 hour 42 hour

4 hours after 6th dose = 40 hours

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Problems with missed dose

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 Problems with missed dose
• Before reaching steady state
__

• tmiss is time elapsed since scheduled dose was missed

• If steady state is reached

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 Problems with missed dose
(a) the fifth dose was omitted,
tmiss = 6 + 4 = 10 hours
= 1.353 mg/L
Cp = 6.425 - 1.353 = 5.072 mg/L
(b) the sixth dose was omitted,
tmiss = 4 hours

Cp = 6.425 – 4.493 = 1.932 mg/L

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 Problems with missed dose

(c) the fourth dose was omitted?

tmiss = 6+6+4 = 16 hours

Cp = 6.425 – 0.408 = 6.017 mg/L

The effect of a missing dose becomes less pronounced at a later time. A strict
dose regimen compliance is advised for all drugs. With some drugs, missing a
dose can have a serious effect on therapy. For example, compliance is
important for the anti-HIV1 drugs such as the protease inhibitors
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 Early or Late Dose Administration during Multiple Dosing

• When one of the drug doses is taken earlier or later than

scheduled, the resulting plasma drug concentration can still
be calculated based on the principle of superposition.
• The dose can be treated as missing, with the late or early dose
added back to take into account the actual time of dosing.

• tmiss = the time elapsed since the dose (late or early is scheduled).
• tactual = time elapsed since the dose (late or early) is actually taken.

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 tmiss = ? tmiss = 6+6+4 = 16

tactual = ? tactual = 4+6+4 = 14

Loading 1st 2nd 3rd 3rd 4th 4th 5th 6th 7th
dose dose dose dosedose dose dose dose dose dose
40 hour

0 hour 6 hour 12 hour 16 hour

18 hour 26 hour
24 hour 30 hour 36 hour 42 hour

4 hours after 6th dose = 40 hours

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 Early or Late Dose Administration during Multiple Dosing

A cephalosporin (k = 0.2 h-1, VD = 10 L) was

administered by IV multiple dosing; 100 mg was
injected every 6 hours for 6 doses. What was the
plasma drug concentration 4 hours after the
sixth dose (ie, 40 hours later) if
(a) the fifth dose was administered 2 h late,
(b) the sixth dose was administered 1 h early,
(c) the fourth dose was administered 3 h late?

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 Early or Late Dose Administration during Multiple Dosing

• the fifth dose was administered 2 h late,

• tmiss = 10 h, tactual = 8 h

𝐷0 𝑒 −𝑘𝑡 𝐷0 −𝑘𝑡𝑚𝑖𝑠𝑠 𝐷0 −𝑘𝑡𝑎𝑐𝑡𝑢𝑎𝑙

𝐶𝑝 = − 𝑒 + 𝑒
𝑉𝑑 1 − 𝑒 −𝑘τ 𝑉𝑑 𝑉𝑑
100 𝑒 −0.2 𝑋 4 100 −0.2 𝑋 10 100 −0.2 𝑋 8
𝐶𝑝 = − 𝑒 + 𝑒
10 1 − 𝑒 −0.2 𝑋 6 10 10
𝐶𝑝 = 6.425 – 1.353 + 2.01 = 7.082 mg/L

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 Early or Late Dose Administration during Multiple Dosing

• the 6th dose was administered 1 h early

• tmiss = 4 h, tactual = 5 h

𝐷0 𝑒 −𝑘𝑡 𝐷0 −𝑘𝑡𝑚𝑖𝑠𝑠 𝐷0 −𝑘𝑡𝑎𝑐𝑡𝑢𝑎𝑙

𝐶𝑝 = − 𝑒 + 𝑒
𝑉𝑑 1 − 𝑒 −𝑘τ 𝑉𝑑 𝑉𝑑
100 𝑒 −0.2 𝑋 4 100 −0.2 𝑋 4 100 −0.2 𝑋 5
𝐶𝑝 = − 𝑒 + 𝑒
10 1 − 𝑒 −0.2 𝑋 6 10 10
𝐶𝑝 = 6.425 – 4.49 + 3.68 = 5.615 mg/L

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 Early or Late Dose Administration during Multiple Dosing

• the 4th dose was administered 3 h late

• tmiss = 16 h, tactual = 13 h

𝐷0 𝑒 −𝑘𝑡 𝐷0 −𝑘𝑡𝑚𝑖𝑠𝑠 𝐷0 −𝑘𝑡𝑎𝑐𝑡𝑢𝑎𝑙

𝐶𝑝 = − 𝑒 + 𝑒
𝑉𝑑 1 − 𝑒 −𝑘τ 𝑉𝑑 𝑉𝑑
100 𝑒 −0.2 𝑋 4 100 −0.2 𝑋 16 100 −0.2 𝑋 13
𝐶𝑝 = − 𝑒 + 𝑒
10 1 − 𝑒 −0.2 𝑋 6 10 10
𝐶𝑝 = 6.425 – 0.407 + 0.743 = 6.76 mg/L

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 Early or Late Dose Administration during Multiple Dosing

A dose of 600 mg of drug “X” is administered

every 8 hours for 8 doses through IV bolus
injection. The half life of drug is 6 hours and
volume of distribution is 20 L. What was the
plasma drug concentration 3 hours after the
sixth dose if
(a) the fifth dose was administered 4 h late,
(b) the sixth dose was administered 4 h early,
(c) the fourth dose was administered 3 h late?
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 Intermittent IV Infusion
• Intermittent IV infusion is a method of successive
short IV drug infusions in which the drug is given
by IV infusion for a short period of time followed
by a drug elimination period.
• Then followed by another short IV infusion.
• The rationale for intermittent IV infusion is to
prevent transient high drug concentrations and
accompanying side effects.
• Many drugs are better tolerated when infused
slowly over time compared to IV bolus dosing
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Administering One or More Doses by Constant Infusion: Superposition of
Several IV Infusion Doses
IV Infusion (Single Dose)
𝐶
C(t)= 𝑅𝑎𝑡𝑒 1 − 𝑒⎼𝑘𝑡1 𝑒⎼𝑘𝑡2
𝑘
During Infusion
t1 = time
t2 = 0
After infusion
t1 = duration of infusion
t2 = time after infusion

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 Example
• An antibiotic was infused with a 40-mg IV dose
over 2 hours. Ten hours later, a second dose of
40 mg was infused, again over 2 hours. The
elimination rate constant is 0.2 h-1 and Vd is 10 L
(a) What is the plasma drug concentration 2 hours
after the start of the first infusion?
(b) What is the plasma drug concentration 5 hours
after the second dose infusion was started?

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 First Infusion
• The plasma drug conc. at the completion of first Infusion
𝐷𝑜𝑠𝑒
Cp= 1 − 𝑒⎼𝑘𝑡1 𝑒⎼𝑘𝑡2
𝑡𝑖𝑛𝑓 .𝑘.𝑉𝑑
40 −0.2×2 ⎼0.2 × 0
Cp= 1−𝑒 𝑒
2×0.2×10
Cp= 3.30 𝑚𝑔/𝐿
• The plasma drug conc at 15 h after the start of first Infusion
t2 = ??? t2 = 13

Cp= 𝐶𝑠𝑡𝑜𝑝 𝑒 −𝑘𝑡2 Cp= 3.30 𝑒 −0.2×13 = 0.25 mg/L

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 2nd Infusion
• The plasma drug conc. at 5 h after the start of 2nd Infusion
t2 = ??? t2 = 3

Cp= 𝐶𝑠𝑡𝑜𝑝 𝑒 −𝑘𝑡2 Cp= 3.30 𝑒 −0.2×3 = 1.81 mg/L

• Total plasma drug conc. at 5 h after the start of 2nd Infusion

Cp = 0.25 + 1.81 = 2.06 mg/L

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 Example
An antibiotic was infused with a 100 mg IV dose
over 3 hours. Twelve hours later, a second dose of
100 mg was infused, again over 3 hours. The
elimination rate constant is 0.2 h-1 and Vd is 20 L
(a) What is the plasma drug concentration 4 hours
after the start of the first infusion?
(b) What is the plasma drug concentration 6 hours
after the end of second dose infusion?

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 Multiple oral dosage regimen
𝐾𝑎
Cp = 𝐷𝑜𝑠𝑒 × 𝐶 𝑒⎼𝑘𝑡 − 𝑒⎼𝑘𝑎𝑡
(𝑘𝑎−𝑘)
Before Steady state
IV Bolus

Oral

After Steady state

IV Bolus

Oral
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 Multiple oral dosage regimen
• An adult male patient (46 years old, 80 kg) was given 250 mg of
tetracycline hydrochloride orally every 8 hours for 2 weeks. From the
literature, tetracycline hydrochloride is about 75% bioavailable and has an
apparent volume of distribution of 1.5 L/kg. The elimination half-life is
about 10 hours. The absorption rate constant is 0.9 h-1. From this
information, calculate
a) Plasma concentration at 5 hours after administration of 3rd dose
b) Plasma concentration at 4 hours after administration of 7th dose

K = 0.693/10 = 0.07
Vd = 1.5 X 80 = 120 L

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 Plasma concentration at 5 hours after administration of 3rd dose

0.9×0.75×250 1−𝑒 −3×0.07×8 −0.07×5 1−𝑒 −3×0.9×8 −0.9×5

Cp = ( )𝑒 − ( )𝑒
120 (0.9−0.07) 1 − 𝑒 −0.07×8 1 − 𝑒 −0.9×8

168.75 1−𝑒 −3×0.07×8 −0.07×5 1−𝑒 −3×0.9×8 −0.9×5

Cp = ( )𝑒 −( )𝑒
99.6 1 − 𝑒 −0.07×8 1 − 𝑒 −0.9×8

Cp = 1.694 1.33 − 0.0111 = 2.23 𝑚𝑔/𝐿

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Plasma concentration at 4 hours after administration of 7th dose

Cp = 1.694 1.76 − 0.0273 = 2.93 𝑚𝑔/𝐿

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 Loading Dose
• Loading dose is the dose of drug that is given to reduce
the onset time of drug and to achieve desired plasma
concentration as early as possible.
• If the drug follows one-compartment pharmacokinetics,
then the steady state is also achieved immediately
following the loading dose.
• Thereafter, a maintenance dose is given to maintain
average steady state concentration so that the
therapeutic effect is also maintained.
• In practice, a loading dose may be given as a bolus dose
or a short-term loading IV infusion.

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 Loading Dose
• The loading dose should approximate the amount of
drug contained in the body at steady state.

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 Loading Dose
• Calculate the loading dose for a drug which is
effective at steady state concentration of 15
mg/L and the volume of distribution is 40 L
• Also calculate maintenance dose if half life of
drug is 6 hours and dose interval is 6 hours.
DL = 15 mg/L X 40 L = 600 mg
CL = 0.1155 h-1 X 40 L = 4.62 L/h
Maintenance Dose = 15 mg/L X 4.62 L/h X 6 h = 415.8 mg

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Thank you…

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