Basic principles

of
Pharmacokinetics
Ja mila h A ln a h d i , Ph a rm
D. MSc, Clinical
Pharmacy.
Senior scienti fi c
evaluati on specialist at
SFDA.
Outlines
:Introduction

 Mathematical models
 Rates and Orders of Reactions
 Half-life and elimination rate constant
 Bioavailability & bioequivalence
 Absorption
 Protein Binding & Volume of distribution
 Clearance
Introduction:
PK:
What the body does to the drug?
• The science of the kinetics of drug absorption, distribution, and elimination.
Also referred as ADME
PD:
What the drug does to the body?
• The relationship between the drug concentration at the site of action
(receptors) and pharmacologic response.
Introduction:
•The objective of clinical PK is to design safe and effective dosage regimens for
patients.
•To produce a desired drug concentration in the body using the optimum dosage
regimen and dosage form
Introduction:
Dosage regimen means:
•Dose (How much drug?)
•Dosing interval (How often?)
•(How long?)
•Method of administration (IV or oral)
•Type of formula (rapid vs extended release) (dosage form)
Conc–time
curve after oral
administration
of a drug
 Cmax Conc–time
curve
showing peak
time and
concentration.
Tmax
One-compartment model
One-compartment model
The one-compartment open model assumes that:

◦ 1. The drug is introduced all at once in the systemic circulation (i.e. all
the drug enters into the circulation immediately).
◦ 2. There is rapid distribution of the drug in the plasma (or blood).

◦3. There is rapid equilibrium established between drug in plasma (or blood)
and drug in tissues (doesn’t mean equal concentrations in plasma and
tissues).
◦4. The process of drug elimination is by a first-order (linear) kinetic process.
 Two Compartment
•Model
Instead of being monophasic, it is biphasic.

• A drug follows this model does not equilibrate rapidly throughout the body.
The drug distributes into 2 compartments, central and peripheral.
One vs. two compartment model

One compartment

Log C

Two compartments

Time
One vs. two compartment model
 When distribution is more rapid than elimination, kinetic behavior is
described by a one-compartment model
 When distribution is sufficiently slow that a significant fraction of dose is
eliminated before distribution equilibrium is achieved, kinetic behavior is
described by a two-compartment model
 Rates and Orders of
Reactions:
Zero-order reactions
 First-order reactions
 Zero-order reactions:
Zero-order reactions:
- The change in drug concentration is independent
of the concentration.
- Same amount of drug is eliminated per unit
time.
•A = -k0t + A0
• C = - k0 t + C 0
•Slope = -K0
Zero-order reactions:
First-order reactions:
First-order reactions:
- The change in drug concentration is dependent
of the concentration.
- Same fraction of drug is eliminated per unit time.

•ln C = -kt + ln C0  ln = 2.3 log  log C = −𝑘 𝑡 + log 0

2.3
C = C × 𝑒−𝑘𝑡
•C 0

•Slope = −𝑘
2.3
First-order reactions:
Example1
: Drug Concentration (mg/mL) Time (hr)
100 0
95 2
90 4
85 6
80 8
75 10
70 12

Find C0 ,C at 6 hr and k?
Example1
:
C = 100 mg/L
0

C at 6 hr = 85 mg/L
K = - slope
95−90 5 𝑚 𝑔 𝑙𝐿
K=- =- = 2.5
2−4 −2 ℎ𝑟
Zero-order vs. first
orderNormal graph Semi-log graph

Zero order constant amount per time

First order constant fraction per time
 Half-
•life:
T1/2 of a drug is the time required for a given concentration to decrease by
50%.
•It is an important PK parameter because it characterizes the stay of drug in
the
body.
Example1
: Drug Concentration (mg/mL) Time (hr)
100 0
95 2
90 4
85 6
80 8
75 10
70 12

Find t1/2?
Example1
: = 100 mg/L
C0

C at 6 hr = 85
mg/L K = - slope
95−90 5 𝑚 𝑔𝑙
K=- =- = 2.5 𝐿
2−4 −2 ℎ𝑟
T1/2= (0.5 C0)/k
= (0.5 ×100)/2.5
= 20 hr
Example2
:mg/L
If we know that the plasma drug concentration just after gentamicin dose is 8
and the patient’s elimination rate constant is 0.25 hr-1,
Find t1/2?
C = C0 × 𝑒−𝑘𝑡
C0 = 8 mg/L , k = 0.25 hr-1
0.693
T1/2= 𝑘
= 2.772 hr.
Bioavailability:
 Bioavailabilit
•y:
It is the fraction (F) of an extravascular dose that gets to the central blood
compartment (absorbed).
•It represents the rate and extent of absorption of an active drug ingredient and
becomes available at the site of action in order to produce a therapeutic effect.
•For IV usually = 1 or 100%
Bioavailabilit
y:
Bioavailabilit
y: BA:
Absolute
AUC (oral)
F= (same doses)
AUC (IV)

Dose (IV) ×AUC (oral)

F= (if different doses used)
Dose (oral) ×AUC (IV)
Bioavailabilit
y:
Relative BA:

AUC (test) (different dosage form, same dose)

F=
AUC (ref)

Dose (ref) ×AUC (test)

F= (different dosage form and dose)
Dose (test)×AUC (ref)
Exampl
e:
Drug product Dose AUC (mg/L x hr)
Capsule 150 76.1
Suspension 150 89.5
IV bolus 50 37.8

Calculate:

1 Oral bioavailability (%) of the suspension product

2 Oral relative bioavailability (%) of the capsule product
Exampl
e:Oral bioavailability
1- (%) of the suspension product
Dose (IV) × AUC (oral)
F= (if different doses used)
Dose (oral) × AUC
(IV) 50× 89.5
F=
150×
37.8
F= 4475
5670
F = 0.79 = 79%
Exampl
e:Oral relative bioavailability (%) of the capsule product
2-
AUC (test) (different dosage form, same dose)
F=
AUC (ref)
F= 76.1

89.5
F = 0.85 = 85%
Bioavailabilit
y: it is important?
Why

Variability?
 Bioavailabilit
y:can calculate the Amount of drug absorbed by using F.
You
Example:
Bioavailability of 200mg phenytoin tablet is 70%
The absorbed dose = 0.7 X 200 mg
= 140 mg.
Bioequivalence:
 Bioequivalence
: Healthy subjects ( usually24 to 36 adults.)
 Non smokers
 Ages of 18 to 35 years are preferred.
 Normal weights
 Manufacturer must show that the ratio of the (AUC, Cmax) of its product
(test) compared to that of the innovator (reference) product is within
the limits of 0.8 to 1.2 (80% - 125%).
Bioequivalence
:
 Absorption
•:
Drugs given orally usually absorbed via first order process.
•Absorption rate constant or ka indicates the fraction of drug present at the
absorption site (usually GI tract) that is absorbed per unit of time.
•Higher the value, faster the absorption.
Absorption
:the rate of drug absorption (k ).
The plasma concentrations achieved can be controlled by
a

Formula I

Formula II

Formula III
 Protein
•Binding:
Only free fraction of drug moves freely between different tissues and exhibit
pharmacological effect.
•Also its available for distribution and elimination.
Protein
Binding:
If Protein binding decrease, free drug is increase.

Give example ?
Volume of Distribution
(Vd):
Higher Vd, more distribution
and slower elimination
 Clearance
•(CL):
Drug elimination is usually described in terms of Clearance (Cl)
•It is defined as the volume of blood from which the drug is eliminated per unit
of time.
•The units for clearance are sometimes in milliliters per minute (mL/min) or
(L/h).
 Clearance
(CL):
•T1/2 is inversely proportional to the clearance of a drug (Cl).

• Cl very important clinically, it determines the AUC (or total exposure) Cl

= Dose/ AUC
Clearance
(CL): filtration rate:
Glomerular
Normal GFR ~ 125 ml/min
How to measure GFR?

- By using a drug that is eliminated by filtration only (e.g. inulin and creatinine

not bound to proteins)  neither reabsorbed nor secreted.
 Clearance of creatinine = GFR = ~125
 Clearance
•(CL):
GFR is reduced in: newborn, elderly, kidney and heart..
•If GFR is reduced: lower drug dose, increase dose interval or
both.
Question 1:
A 50-kg woman was given a single IV dose of an antibacterial drug at a dose level
of 6 mg/kg. Blood samples were taken at various time intervals. The
concentration of the drug (Cp) was determined in the plasma fraction of each
blood sample and the following data were obtained:
t (hours) Cp (µg/mL)
0 8.4
0.25 8.21
0.50 7.87
1.00 7.23
3.00 5.15
4.00 4.2
12.0 1.11
18.0 0.40
Question 1:
1. What are the values for VD, k, and t1/2 for this drug?
VD= 35.7 L, t1/2= 4 hr, k= 0.173 hr-1
2.This antibacterial agent is not effective at a plasma concentration of less than
2 μg/mL. What is the duration of activity for this drug?
C = C0 × 𝑒−𝑘𝑡  2 = 8.4 × 𝑒−0.173𝑡  t = 8.29 hr.
3.How long would it take for 99.9% of this drug to be eliminated?
C = C0 × 𝑒 −𝑘 𝑡  0.0084 = 8.4 × 𝑒 −0.173𝑡  t= 39.9 hr.
Question 1:
4. If the dose of the antibiotic was doubled exactly, what would be the increase
in duration of activity?
If the dose is doubled, then C0 will also double. However, the elimination half-
life or first-order rate constant will remain the same. Therefore,
C = C0 × 𝑒−𝑘𝑡  2 = 16.8 × 𝑒−0.173𝑡  t = 12.3 hr.
Notice that doubling the dose does not double the duration of activity.
Question 2:
A new antibiotic drug was given in a single intravenous bolus of 4 mg/kg to
healthy male adult (weight 75 kg). The pharmacokinetics of the plasma drug
concentration–time curve for this drug fits a one-compartment model. The
equation of the curve that best fits the data is

Determine the following (assume units of μg/mL for Cp and hours for t):
a. What is the t1/2?
b. What is the VD?
c. What is the plasma level of the drug after 4 hours?
d. How much drug is left in the body after 4 hours?
e.Predict what body water compartment this drug might occupy and explain why
you made this prediction.
Question 2:
a. What is the t1/2?

b. What is the VD?

c. What is the plasma level of the drug after 4 hours?

= 12.38 μg/mL
d. How much drug is left in the body after 4 hours?
Dose = C×V = 12.38×3846 = 47613.48 μg = 47.61 mg.
Question 2:
d. Predict what body water compartment this drug might occupy and explain why
you made this prediction.
Vd= 3846 mL = 3.8 L
The apparent VD approximates the plasma volume.
Thank you..
Any Question?
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