1. PHT 415 BASIC PHARMACOKINETICS
Textbook:
Applied Biopharmaceutics and pharmacokinetics

2. Objectives of the first 2 lectures (Introduction)
To understand and define the basic pharmacokinetic parameters and their applications.
To be familiar with the important pharmacokinetic concepts

3. Introduction
A simple definition of pharmacokinetics is the study of the time course of drug concentration in the body (what the body does to the drug)
Pharmacokinetic processes include absorption, distribution, elimination (metabolism and excretion)

4. Introduction
Pharmacodynamics: The study of the relationship between drug concentration in the body and its pharmacological response (what the drug does to the body)

5. Introduction
Biopharmaceutics is the study of the relationship between the physicochemical properties of the drug, dosage form in which the drug is given, and the route of administration; and the rate and extent of systemic drug absorption

6. Introduction
Sites of drug administration may be classified as intravascular or extravascular.
Intravascular administration refers to the placement of a drug directly into the blood, either intravenously or intra-arterially.
Extravascular include the oral, sublingual, buccal, intramuscular, subcutaneous, dermal, pulmonary, and rectal routes.

7. Introduction Drugs administered extravascularly must be absorbed.
Absorption may be defined as the movement of drug molecules from the site of administration to the blood circulation, in order for a drug to be absorbed, it has to be released from dosage form and converted into solution.

8. Introduction
Disposition may be defined as the processes that occur subsequent to the absorption of a drug. Therefore, the components of disposition are distribution and elimination.

9. Introduction
Once absorbed, a drug may be distributed to the various organs of the body. Distribution is influenced by the organ blood perfusion, organ size, binding of drug within blood and tissues, and permeability of tissue membranes.

10. Introduction
Distribution describes the reversible diffusion or transfer of drug molecules from intravascular space to body tissues.
Elimination is the irreversible loss of drug from the body by metabolism or excretion.

11. Introduction
Metabolism describes the conversion of drugs into metabolites by enzymes (metabolites are usually more polar compounds that are more easily excreted).
The major site of metabolism is the liver but it may occur in some other organs such as intestines, lungs and kidneys.

12. Introduction
Excretion is the irreversible loss of chemically unchanged drug.
The kidneys are the primary site for excretion of most of the chemically unchanged drugs. However, some drugs are excreted by other routes such as the bile.

13. Introduction Mass balance of a drug with time in the body:
Dose = amount of drug at absorption site + amount of drug in the body + amount of drug eliminated (by metabolism and excretion)

14. Introduction
Studying the pharmacokinetics of any drug requires the measurement of drug concentration in a suitable biological fluid such as plasma, serum, blood or urine at appropriate time intervals using a valid analytical method (validation should cover sensitivity, linearity, specificity, recovery, accuracy, precision and stability)

15. Introduction
The most direct and commonly used approach for assessing drug pharmacokinetics is based on the measurement of drug concentration in the whole blood, serum or plasma.
Serum is obtained by allowing the whole blood to clot and the serum is collected from the supernatant after centrifugation.
Plasma is the supernatant of centrifuged whole blood to which an anticoagulant, such as heparin, was added.

16. Introduction Plasma concentration - time curve:
It Is generated by measuring the drug concentration in plasma samples taken at various time intervals after a drug product is administered
The concentration of drug in each plasma sample is plotted against the corresponding time at which the plasma sample was collected.

17. Introduction

18. Introduction Pharmacokinetic modeling:
Mathematical models can be used to describe drug absorption, distribution, and elimination based on drug concentration (a dependent variable) in the body as a function of time (an independent variable).

19. Pharmacokinetic models may be used to:
predict plasma , tissue, or urine drug levels with any dosage form
calculate the optimum dosage regimen for each patient individually
correct drug concentrations with pharmacological or toxicological activity
evaluate differences in the rate or extend between formulations ( Bioequivalence studies)
study drug interactions

20. Event that follows drug administration
Plasma conc of theophylline after an oral dose of 600-mg

21. OPTIMIZE PATIENT DRUG THERAPY BY MONITORING PK&PD RESPONSES
Aimes of PK and PD
Knowing the PK and PD of drugs will aid
in designing a dosage regimen to achieve
the therapeutic objective.
OPTIMIZE PATIENT DRUG THERAPY BY MONITORING PK&PD RESPONSES

22. Advantages over the Empirical Approach
1- Distinction can be made between PK and PD causes of an unusual drug response.
2- Information gained about the PK of one drug can help in anticipating the PK of another drug.
3- Understanding the PK of a drug often explains the manner of its use.
4- Knowing the PK of a drug aids the clinician in determining the optimal dosage regimen for a patient and in predicting what may happen when a dosage regimen is changed.

23. An Approach to the Design of a Dosage Regimen

24. Where to Measure Concentration?
Rarely can the concentration of the drug at the site of action be measured directly; instead, the concentration is measured at an alternative and more accessible site, the plasma.

25. What is then an optimal dosage regimen?
It is the one that maintains the plasma concentration of a drug within the therapeutic window.

26. Therapeutic Window (TW)
The size and frequency of the maintenance dose depends on the width of the therapeutic window and the speed of drug elimination.
Generally, When the window is narrow and the drug is eliminated rapidly, small doses should be given more often to achieve therapeutic success.
Both cyclosporine and digoxin have a narrow TW, but because cyclosporine is eliminated much more rapidly than digoxin, it has to be given more frequently.

27. Oxytocin
Oxytocin is an extreme example, it also has a narrow TW, but it is eliminated within minutes. The only means to ensure a therapeutic conc is to infuse it at a precise and constant rate directly into the blood (i.v. infusion). Oxytocin can not be given orally because it is destroyed in the GIT.
Morphine can not also be given orally because it is extensively metabolized in the liver.

28. PROBLEM!!! Variability in Clinical Response
Sources of variability include: patient’s age, weight, type and severity of disease, the patient’s genetic makeup, other drugs concurrently administered.
Result: A standard dosage regimen of a drug may prove therapeutic in some patients, ineffective or even toxic in others.

29. Dosage Regimen Adjustment
Especially for drugs with narrow TW such as:
Digoxin
Phenytoin
Theophylline
Cyclosporine
Warfarin

30. Drug-Drug Interaction
Interactions that result in a change in PK of a drug could be due to interference with :
drug absorption.
drug distribution.
drug excretion.
drug metabolism.

31. WHAT WE WILL DO IN THIS CLASS?
Although the details of drug kinetics are complicated, it is fortunate that we can often approximate drug kinetic processes using “SIMPLE MATHEMATICAL MODELS”.
The use of PK equations, rather than the derivation of the equations will be taught in this class.