1 University of Jordan-Faculty of Pharmacy Department of Biopharmaceutics and Clinical Pharmacy Semester: First Course Title: Pharmacokinetics Course Code:1203475.

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University of Jordan-Faculty of PharmacyDepartment of Biopharmaceutics and Clinical PharmacySemester: FirstCourse Title: PharmacokineticsCourse Code: 1203475Prerequisite: Biopharmaceutics (1203471)Instructor: Dr. Mohammad Issa

Name Office #

Office Hours E - mail

Dr. Mohammad Issa 230 Sun 12-1Tue 11-12

Moh.saleh@ju.edu.jo

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Course Objectives :1) Understanding mathematical background for modeling of the concentration time relationships for the different routes of administration.2) Designing dosing regimens by relating plasma concentration of drugs to their pharmacological and toxicological action,3) Understanding the concept of therapeutic drug monitoring for drugs with narrow therapeutic range or high toxicity.

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Learning Outcomes :A) Knowledge and understandingA1) Understanding mathematics of the time course of Absorption, Distribution, Metabolism, and Excretion (ADME) of drugs in the body.A2) Understanding Individualization of therapy and therapeutic drug monitoring.

B) Intellectual skills (cognitive and analytical)B1) Utilization of mathematics of the time course of Absorption, Distribution, Metabolism, and Excretion (ADME) of drugs in the body for dosage optimization.B2) Developing dosing regimens for the individualization of therapy for the patient

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C) Subject specific skillsC1) Fitting concentration time profiles and estimating pharmacokinetic parameters.C3) Designing dosing regimens in case of renal and hepatic dysfunction.D) Transferable SkillsD1) Communicating the dosage adjustment with physicians.D2) Suggesting therapeutic monitoring plans.

Teaching Methods :1) Lectures2) Computer software (demo)3) Case Studies

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Tests & Evaluations :

Midterm exam 40% Quizzes and HWs 10% Final exam 50%

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1. Introduction2. The one-compartment open model with an intravenous bolus dose.Plasma data; elimination rate constant, AUC, elimination half-life, volume of distribution and clearanceUrinary data; excretion rate constant and half-life, elimination rate constant3. The one-compartment open model with an intravenous infusion. Continues infusion, Infusion with a bolus dose, post infusion 4. The one-compartment open model with absorption and elimination; Absorption rate constant, calculation of F, method of residuals, flip-flop kinetics5. The one-compartment open model with multiple dosing kinetics; Multiple dosing IV and oral, multiple dosing factor, accumulation factor, loading dose, and average concentration. 6. Designing dosing regimens 7. Dosage adjustment in renal failure. (Aminoglycosides)8. The two-compartment open model with intravenous administration.9. Non-linear pharmacokintics Michaels-Mention kinetics, methods to obtain Vmax and Km (Phenytoin).10. Pharmacodynamics Linear models, E-max and time dependent response.11. Therapeutic Drug Monitoring.12. Bioequivalence revisited.

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Textbook:Applied biopharmaceutics and pharmacokineticsShargel and Yu, 5th edition, 2005References:1) Pharmacokinetics: processes, mathematics, and applications 2nd edition, Welling, P.G.., 19972) Handbook of Basic PharmacokineticsWolfgang Ritschel, 6th edition, 20043) Clinical pharmacokinetics: concepts and applicationsRowland and Tozer, 3rd edition, 1995Useful Web Sites1) PHARMACOKINETICS LECTURE NOTES ONLINEhttp://www.healthsci.utas.edu.au/pharmacy/kinetics/main.htm2) University of Alberta/ Dr. Jamalihttp://www.pharmacy.ualberta.ca/pharm415/contents.htm3) A First Course in Pharmacokinetics and Biopharmaceuticshttp://www.boomer.org/c/p1/

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Pharmacokinetics: Introduction

Dr Mohammad Issa

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What is pharmacokinetics?

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What is pharmacokinetics?

Pharmacokinetics is the study of kinetics of absorption, distribution, metabolism and excretion (ADME) of drugs and their corresponding pharmacologic, therapeutic, or toxic responses in man and animals’’ (American Pharmaceutical Association, 1972).

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Review of ADME processes

ADME is an acronym representing the pharmacokinetic processes of:

A AbsorptionD DistributionM MetabolismE Excretion

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Review of ADME processes

Absorption is defined as the process by which a drug proceeds from the site of administration to the site of measurement (usually blood, plasma or serum)

Distribution is the process of reversible transfer of drug to and from the site of measurement (usually blood or plasma)

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Review of ADME processes

Metabolism is the process of a conversion of one chemical species to another chemical species

Excretion is the irreversible loss of a drug in a chemically unchanged or unaltered form

Metabolism and excretion processes represent the elimination process

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Applications of pharmacokinetics

bioavailability measurements effects of physiological and pathological

conditions on drug disposition and absorption dosage adjustment of drugs in disease states, if

and when necessary correlation of pharmacological responses with

administered doses evaluation of drug interactions clinical prediction: using pharmacokinetic

parameters to design a dosing regimen and thus provide the most effective drug therapy

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Applications of pharmacokinetics

Bioavailability measurements: Blood sulfadiazine concentration in human following the administration of a 3 g dose. A comparison of the behavior of microcrystalline sulfadiazine with that of regular sulfadiazine in human

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Applications of pharmacokinetics

Effects of physiological and pathological conditions on drug disposition and absorption: plasma conc-time profile of cefepime after a 1000 mg IV infusion dose

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Applications of pharmacokinetics

Using pharmacokinetic parameters to design a dosing regimen and thus provide the most effective drug therapy

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Rates and orders of reactions

The rate of a chemical reaction of process is the velocity with which the reaction occurs. Consider the following chemical reaction:

If the amount of drug A is decreasing with respect to time (that is, the reaction is going in a forward direction), then the rate of this reaction can be expressed as

Since the amount of drug B is increasing with respect to time, the rate

of the reaction can also be expressed as

The rate of a reaction is determined experimentally by measuring the disappearance of drug A at given time intervals.

B drug A drug

dt

dA

dt

dB

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Zero-Order Reactions

Consider the rate of elimination of drug A from the body. If the amount of the drug, A, is decreasing at a constant rate, then the rate of elimination of A can be described as:

where k* is the zero-order rate constant.

The reaction proceeds at a constant rate and is independent of the concentration of A present in the body. An example is the elimination of alcohol

*kdt

dA

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Zero-Order Reactions

The amount of a drug with zero order elimination is described according to the following equation:

where A is the amount of drug in the body, A0 is the amount of the drug at time zero (equal to the dose in the case of IV bolus)

tkAA *0

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Drug with zero order PK

Slope = -K*

A0

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Zero-Order Reactions: example

The administration of a 1000 mg of drug X resulted in the following concentrations:

TimeConc. (mg/L)

0 100

4 90

6 85

10 75

12 70

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Zero-Order Reactions: example

What is the order of the elimination process (zero or first)?

What is the rate constant?

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Zero-Order Reactions: example

y = -2.5x + 100

R2 = 1

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14

time (hr)

con

c (m

g/L

)

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Zero-Order Reactions: example

Since the decline in drug conc. Displayed a linear decline on normal scale, drug X has a zero order decline

From the equation displayed on the figure (intercept = 100, slope = -2.5)

The elimination rate constant is 2.5 mg/hr

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First-order Reactions

If the amount of drug A is decreasing at a rate that is proportional to A, the amount of drug A remaining in the body, then the rate of elimination of drug A can be described as:

where k is the first-order rate constant

The reaction proceeds at a rate that is dependent on the concentration of A present in the body

It is assumed that the processes of ADME follow first-order reactions and most drugs are eliminated in this manner

AKdt

dA

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First-Order Reactions

The amount of a drug with first order elimination is described according to the following equation:

where A is the amount of drug in the body, A0 is the amount of the drug at time zero (equal to the dose in the case of IV bolus)

This equation is equivalent to:

tkeAA *0

tkAA *)ln()ln( 0

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Drug with first order PK

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Drug with first order PK:log transformation

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Nonlinear kinetics

Nonlinear pharmacokinetics is also known as dose-dependent and concentration dependent pharmacokinetics because the pharmacokinetic parameters are dependent on the drug concentration or the drug amount in the body

At least one of the absorption, distribution, and elimination processes, which affect the blood drug concentration—time profile, is saturable and does not follow first-order kinetics

The change in drug dose results in disproportional change in the blood drug concentration— time profile after single- and multiple-dose administrations

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Nonlinear kinetics

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Nonlinear kinetics

Linear kinetics:

CKdt

dC

Nonlinear kinetics:

CK

CV

dt

dC

m max

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Linear vs nonlinear PK Linear PK Nonlinear PK

1-Known as dose-independent or concentration-independent PK.

1-Known as dose-dependent or concentration-dependent PK.

2-The absorption, distribution and elimination of the drug follow first-order kinetics

2-At least one of the PK processes (absorption, distribution or elimination) is saturable.

3-The pharmacokinetic parameters such as the half-life, total body clearance and volume of distribution are constant and do not depend on the drug conc

3-The pharmacokinetic parameters such as the half-life, total body clearance and volume of distribution are conc-dependant

4-The change in drug dose results in proportional change in the drug concentration.

4-The change in drug dose results in more than proportional or less than proportional change in the drug conc.

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Laplace transformation

Optional material

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Laplace transformation

The Laplace transform is a mathematical technique used for solving linear differential equations (apparent zero order and first order) and hence is applicable to the solution of many equations used for pharmacokinetic analysis.

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Laplace transformation procedure

1. Write the differential equation

2. Take the Laplace transform of each differential equation using a few transforms (using table in the next slide)

3. Use some algebra to solve for the Laplace of the system component of interest

4. Finally the 'anti'-Laplace for the component is determined from tables

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Important Laplace transformation (used in step 2)

Expression Transform

dX/dt

K (constant)

X (variable)

K∙X (K is constant)

0XXs

s

K

X

XK

where s is the laplace operator, is the laplace integral

, and X0 is the amount at time zero

X

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Anti-laplce table (used in step 4)

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Anti-laplce table continued (used in step 4)

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Laplace transformation: example

The differential equation that describes the change in blood concentration of drug X is:

Derive the equation that describe the amount of drug X??

*kdt

dA

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Laplace transformation: example

1. Write the differential equation:

2. Take the Laplace transform of each differential equation:

*kdt

dX

s

kXXs

*0

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Laplace transformation: example

3. Use some algebra to solve for the Laplace of the system component of interest

4. Finally the 'anti'-Laplace for the component is determined from tables

20 *

s

k

s

XX

tkXtX *)( 0

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Laplace transformation: example

The derived equation represent the equation for a zero order elimination

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