1 APPLIED BIOPHARMACEUTIS AND PHARMACOKINETICS

Module 1 – Lesson 2
Made by: KAVJ

MATHEMATICAL FUNDAMENTALS IN PHAMACOKINETICS - The log of a number greater than 1 is a positive number
STUDYING THE MATHEMATICAL FUNDAMENTALS
- Biopharmaceutics and Pharmacokinetics
o Involves calculations since BPMC and PK
have a strong mathematical basis
- Needed mathematical principles
o Algebra
o Calculus
o Exponentials
o Logarithms
o Unit analysis

NUMBER EXPONENTIAL log

EXPONENTS AND LOGARITHMS FORM
1,000,000 10^6 6
100 10^2 2
EXPONENTS
- Consider the following expression: NUMBER EXPONENTIAL ln
o N = b^x (e.g.,1000 = 10³) FORM
o x, the exponent 7.389 e^2 2
o b, the base 2 e^0.69 0.69
o N, the number when b is raised to the xth
power
Conversion: LOG to LN
- When the base 10 logarithm scale is used for
expressions containing e
- Done using the factor 2.303
o log 5 = 0.6989
▪ ln 5 = 0.6989 x 2.303 = 1.609
o log 2 = 0.3010
▪ ln 2 = 0.3010 x 2.303 = 0.693

log and ln CALCULUS

COMMON LOGARITHM Calculus

- It is the exponent to which the base must be raised to - An important mathematic tool for analyzing drug
equal a number movement quantitatively since drugs are considered in
- If: N = b^x a dynamic state
- Then: logb N = x
- Example
o 100 = 10^2 - Differential equation
o log 100 = 2 o Used to relate the concentrations of drugs in
o Note: The number 100 is the antilogarithm of various body organs over time
2. - Integrated equation
o Frequently used to model the cumulative
therapeutic or toxic responses of drugs in the
NATURAL LOGARITHM body
- It uses the base e, whose value is 2.718282.
- Related to common logarithms by the equation:
o 2.303 log N = ln N Differential Calculus
- Branch of calculus that involves finding the rate at
which a variable quantity is changing
Things to Know About Logarithms - Example: Dissolution of a specific amount of drug in
- A logarithm does not have units water
- Dimensionless and is considered a real number
- The log of 1 is 0 - The rate at which the drug dissolves is determined by
- Logarithm of a number less than 1 is a negative the rate of drug diffusing away from the surface of the
number solid drug
2 APPLIED BIOPHARMACEUTIS AND PHARMACOKINETICS
Module 1 – Lesson 2
Made by: KAVJ

o [AUC] is the area under the curve

- Expressed by Noyes-Whitney Equation (a differential o tn is the time of observation of drug
equation) concentration, Cn
o tn-1 is the time of prior observation of drug
concentration corresponding to Cn-1

NOYES-WHITNEY EQUATION
- d = denotes a very small change
- X = drug X o [AUC]tn t∞ is the residual area
o Cpn is the last observed plasma
- t = time
concentration at tn
- D = diffusion coefficient
o k is the slope obtained from the terminal
- A = effective surface area of drug
portion
- l = length of diffusion layer
- C1 = surface concentration of drug in the diffusion layer
- C2 = concentration of drug in the bulk solution
- dX/dt = change in X (or a derivative of X) with respect AUC SAMPLE PROBLEM
in t
A dose of 150 mg was administered to healthy volunteer. Seven
blood samples were collected at 0.5, 1, 2, 4, 6, 8, 10 hours.
Differential Calculus and Pharmacokinetics Plasma was separated from each blood sample and analyzed
for drug concentration. The collected data are shown in the table
- The amount or concentration of drug in the body is a below.
variable quantity (dependent variable), and time is
considered to be an independent variable

Integral Calculus
- Integration
o It is the reverse of differentiation
o Considered the summation of f(x) · dx
o The sign ∫ implies summation

Definite Integral
GRAPHS
- A definite integral of a mathematical function is the sum
of individual areas under the graph of that function Graphing
- The construction of a curve or straight line by plotting
observed or experimental data on a graph ¢Important
TRAPEZOIDAL RULE method of visualizing relationships between variables
- A numerical method frequently used in
pharmacokinetics to calculate the area under the The Variables
plasma drug concentration-versus-time curve, called
area under the curve (AUC) - Independent variable (x)
o Placed on the horizontal line in a plane or on
the abscissa (x axis)
o Ex: time
AUC Determination by Trapezoidal
- Dependent variable (y)
Rule Method: IV
o Placed on the vertical line in the plane, or on
- AUC from time 0 to the last the ordinate (y axis)
blood level point determined o Ex: drug concentration
is composed of trapezoids
Types of Graphs

- Formula to be used: 1. Cartesian or rectangular coordinate

2. Semilog graph paper

Straight Line (In a Graph)

3 APPLIED BIOPHARMACEUTIS AND PHARMACOKINETICS
Module 1 – Lesson 2
Made by: KAVJ

- An expression of the linear relationship of x and y POINTS TO REMEMBER

- Very useful for accurately predicting values for which
1. For an equation to be valid, the units or dimensions
there are no experimental observations
must be constant on both sides of the equation
- General equation:
o y = mx + b
o m = slope (gives some idea of the steepness
of the curve)
o b = y intercept

Determination of the Slope

- Slope is equal to Δy/Δx
- As the value of m approaches 0, the line becomes
more horizontal
- As the value of m becomes larger, the line slopes
farther upward or downward, depending on whether m
is positive or negative, respectively

Units for Expressing Blood Concentration

o Drug concentrations should be expressed as
mass/volume
o Examples:
Slope of a Straight Line on a Semilog Graph ▪ mcg/mL
▪ μg/mL
- To determine the slope (m) of a straight line on semilog ▪ mg/L
paper graph, the y values must be converted to ▪ mg% or mg/dL
logarithms
- Formula:
2. In using equations with different units, the units may be
added or subtracted as long as they are alike, but
divided or multiplied if they are different
3. Logarithms and ratios DO NOT HAVE UNITS.
4. Percent may have NO units and is expressed
mathematically as a decimal between 0 and 1 or as 0%
or 100% respectively.
5. Graphs should always have the axes (abscissa and
ordinate) PROPERLY LABELED WITH UNITS.
Graphs and Determination of Order
- The relationship between the x and y data will RATES AND ORDER OF RATE PROCESSES
determine the;
o Order of the process,
o Data quality, PHARMACOKINETICS AND THE RATES OF PROCESSES
o Basic kinetics,
o Number of outliers, and; Rate of Reaction
o Provide basis for an underlying
- The rate of a chemical reaction of a process is the
pharmacokinetic model
velocity with which the reaction occurs
- Example:
o drug A → drug B
o drug A is the parent drug
o drug B is the metabolite
- Usually, only the parent (or pharmacologically active)
drug is measured experimentally
- The rate of a reaction is determined experimentally by
measuring the disappearance of a drug at given time
intervals
4 APPLIED BIOPHARMACEUTIS AND PHARMACOKINETICS
Module 1 – Lesson 2
Made by: KAVJ

Order of a Reaction SAMPLE PROBLEM

- The order of reaction refers to the way in which the A suspension (125mg/mL) decays by zero-order kinetics with a
concentration drug or reactants influences the rate of a reaction rate constant of 0.5mg/mL/hr. What is the concentration
chemical reaction or process of the drug remaining after 3 days?
- Classes:
o Zero-order rate process
o First-order rate process FIRST-ORDER REACTION
- The drug concentration changes with respect to time
Zero-Order Reaction equal the product of the rate constant and the
concentration of drug remaining
- The drug concentration changes with respect to time at - Equivalent mathematical expression:
a constant rate

- Where:
- Where: o C = drug concentration at any time
o C = drug concentration at any time o k = first-order rate constant (units of reciprocal
o k0 = zero-order rate constant (units of time, or time^-1)
concentration per time) o -k / 2.3 = is the slope of the line
= is the slope of the line o C0 = is the y intercept = drug concentration,
o C0 = is the y intercept when time (t) equals zero
= drug concentration, when time (t) equals
zero
*Negative sign = indicates that the slope
is decreasing

Significance of Rate Constants

- Characterize the change of drug concentration in a
particular reference region
- Give the speed at which a drug:
o Enters the compartment (absorption rate
constant, ka)
o Distributes between a central and peripheral
compartments (distribution rate constant)
o Is eliminated from the systemic circulation
(elimination rate constant, k)

First-Order Elimination Kinetics

- A linear process
o rate of elimination is proportional to the drug
concentration
o the elimination
processes are not saturated
Zero-Order Elimination Kinetics and can adapt to the needs
of the body, to reduce
- The Cp vs t profile during the elimination accumulation of the drug
phase is linear o 95% of the drugs
o Example: 1.2 mg are eliminated in use at therapeutic
every hour, independently of the concentrations are
drug concentration in the body. eliminated by first order
- Zero Order elimination is rare elimination kinetics
o mostly occurring when the
elimination system is saturated
o An example is the elimination of
Ethanol
5 APPLIED BIOPHARMACEUTIS AND PHARMACOKINETICS
Module 1 – Lesson 2
Made by: KAVJ

Straight Line HALF-LIFE

Y=mX + b - Expresses the period of time required for the
concentration of a drug to decrease by one half
- Where:
- Is the time required to decrease the initial dose of drug
– Y = Y axis
by 50% (one half of original value)
– m = slope
- Units: time
– X = X axis
– b = y
intercept

SAMPLE PROBLEM

An ophthalmic solution of a mydriatic drug at 5 mg/mL exhibits

Importance of Half-Life
1st order degradation with a k=0.00005/day. How much will
remain after 120 days? - Determine the dosing interval necessary to obtain the
desired Cp of the drug
o Generally, the dosing interval is the same as
COMPARING THE ZERO- AND FIRST-ORDER REACTIONS t½
- Predict how long it will take a drug to reach steady-
ZERO ORDER FIRST ORDER state levels
Equation - Predict the accumulation of a drug in the body for a
dC/dt = k0 dC/dt = kC
specific dosing interval
o During multiple dosing or continuous IV
C = -k0t + C0 C = C0e-kt
infusion it takes approximately 4-5 half-lives
Rate constant – units to reach steady-state levels
(mg/L)/h 1/h - Predict how long it will take a drug concentration to
Half-life, units decrease to a lower concentration
t1/2 = 0.5C/k0 t1/2 = 0.693/k o All drugs are decreased by 96% after 4 half-
(not constant) (constant) lives

Effect of time on rate

First-order rate First-Order Half-Life
will change with
Zero-order rate
respect to time - Is constant for a first-order process
is constant with
as - Is related to the first-order rate constant
respect to time
concentration o No matter what the initial amount or
changes concentration of the drug is, the time required
for the amount to decrease by one half is
Effect of time on rate Rate constant Rate constant constant
constant with respect to remains
time changes constant with
as the respect to time
concentration
changes
Drug concentrations vs
time – plotted on Drug Drug
rectangle coordinates concentrations concentrations
decline linearly decline
nonlinearly

STRAIGHT CURVE

Drug concentrations vs
time – plotted in Drug Drug
semilog graph concentrations concentrations
decline decline linearly
nonlinearly

CURVE STRAIGHT
6 APPLIED BIOPHARMACEUTIS AND PHARMACOKINETICS
Module 1 – Lesson 2
Made by: KAVJ

Zero-Order Half-Life
- Is not constant for a zero-order process
o Is proportional to the initial amount or
concentration of the drug and is inversely
proportional to the zero-order rate constant,
k0

o Because the t½ changes periodically as drug

SAMPLE PROBLEM 3
concentration decline, this has little practical
value A solution of a drug was prepared at a concentration of 300
mg/mL. After 30 days at 25 deg C, the drug concentration in the
solution was 75 mg/mL. assuming 1st order kinetics, compute
for the rate constant.

SAMPLE PROBLEM 4
Determine the half-life of an antihypertensive drug if it appears
to be eliminated from the body at a rate constant of 46% per
hour. Assume 1st order kinetics.

SAMPLE PROBLEM 5
If the half-life for the degradation of a drug is 12 h, compute for
the 1st order rate constant.

PRACTICE PROBLEMS

SAMPLE PROBLEM 1 SAMPLE PROBLEM 6

A pharmacist dissolved 10 g of a drug in 100mL of water. The The half-life of a given drug is 6h. How much remains in the body
solution was kept at room temperature and samples were after one day?
removed periodically and assayed for the drug. Based on the
following data obtained by the pharmacist, compute for the rate
constant: (Use the Table on the next slide)

SAMPLE PROBLEM 2
A pharmacist dissolves exactly 10 g of a drug into 100 mL of
water. The solution is kept at room temperature, and samples
are removed periodically and assayed for the drug. The
pharmacist obtains the following data: