Pharmac Kinetics

7/28/2019 Pharmac Kinetics

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P262 PharmacokineticsIntroduction

J anuary 19, 2011


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Required reading

|Tozer and Rowland text

z Chapter 1


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CLINICAL PHARMACOKINETICS andPHARMACODYNAMICS: Does It Matter?

Paracelsus: 1493-1541

All drugs are poisonous.

Its only a matter of thedose.

The Third Defense, 1537


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What is Pharmacokinetics [PK]?


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What is pharmacokinetics [PK]?-Plot of drug C

versus time

- Study Design:How it wasadministered?Oral, single dose

-To whom? Ahuman

-What issampled, and thefrequency and

duration ofsampling? Bloodcollected, oftenmeasure total

plasma drug C

Drugcon

centration

in

reference

fluid(plasm

a)

time


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Pattern of Cmeasurementsindicate the rates of

increases anddecreases in C

Pharmacokineticistsare interested toquantitate C-t data, toextract PK parameters

that characterize theproperties of the drug

PK is a quantitative science

Drugcon

centration

in

reference

fluid(plasm

a)

time


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What PK properties can we quantitate?

-Drug absorption in theGI tract

-Drug distribution

-Drug metabolism

-Drug excretion

ADME

Drugconc

entrationin

referencefluid(plasma)

time


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Absorption| Process by which drug proceeds from the

site of administration to a site ofmeasurement in body

| For absorption to occur, drug must cross amembrane to reach blood

| Rate of absorption

| Extent of absorption


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Distribution

| Distribution of drug from blood tointra- and extra-cellular fluids

| Blood carrying absorbed drug to the

rest of the body is referred to assystemic circulation

| Distribution is reversible

| Rate and extent of distribution


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Elimination

| Irreversible loss of drug from body

| Blood carries drug to organs of

elimination

|Two processes:

z Metabolism

z Excretion


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|

Metabolismz Enzymes mainly present in liver

z Other eliminating organs: GI tract, lung,

kidney, skin

| Excretion

zThe kidney is the most important organ forexcreting drugs and metabolites

z Substances excreted in feces mainly

unabsorbed drug or drug / metabolitesecreted into bile


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What does the drug concentration-time plot

represent?

Time

PercentofDose

Drug at absorption site

Drug in body

100

50

Excreted drug

Metabolite in body

Excreted metabolite

Look inside the systemto depict ADME.

-Dynamic processes change

over time, can use rateequations to characterize.

-ADME processes are occurring

simultaneously rather thansequentially. At any one time,one process may be dominant.

- However, each drug moleculehas a unique sequential pathin the body.


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GUTLIVER

SYSTEMICCIRCULATION

GI elimination

TISSUES

TISSUES

Drug

excreted

Metabolite

excreted

1155

33

22

44

44

55

Track sequential path ofeach drug and/or metabolitemolecule in body.

Rate of each process [1 thru 5]determine PK parameters andpattern of data or shape ofC-t curve.

5/10 drug is absorbed 2/10 drug is unabsorbed

3/8 drug is metabolized 4/5 drug distributes 2/3 metabolite distr ibutes 5/5 drug is excreted

3/3 metabolite is excreted


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Plasma C-t profiles

IV BolusSingle Oral Dose


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Intermittent Infusion

IV Infusion

Multiple Dosing


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-Nature of PK analysis is dependent

on what is measured and route ofadministration.

-In most clinical PK studies, plasma

drug Cs are available, possibly urine.

- In this example of oral administration,what PK parameters can be obtained?

- Cmax, Cmin, AUC = area under theplasma drug concentration-time curve,and elimination half-life.

-Parameters obtained by eithercompartmental or noncompartmentalmethods.

Approaches to PK Data Analysis

C

t

AUC


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Compartmental Model Approach to

Data Analysis

-In compartmental analysiswe superimpose or apply amathematical model to themeasured C-t data. Typically,

fit a model to the data.

- A model is an equation[s],based on a set of assumptions,

which describes the observedCs; C = f(t). C is a function oftime. The value of C isdependent on time. The model

equation produces the curve.

- From the model equation, wecan calculate PK parameters

such as AUC, and theelimination half-life [t1/2].

1 kka


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-NC analysis is also referred to asmodel-independent analysis, andas implied is not concerned withfitting a model to the observed

Cs.

-Apply mathematical techniquesto extract PK parameters.

Noncompartmental Approach to

Data Analysis

Cmax

Cmin


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Summary Introduction to PK

| PK is the study of ADME

z

Dynamic processes that occursimultaneously and can be cast intorate equations, the solution of which

gives C = f(t).

| PK data analysis consists ofnoncompartmental andcompartmental modeling techniques

that extract PK parameters


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ADME Properties

Hepatic clearance

P450 Metabolism: CYP3A4

Regioselectivity/Lability

Non-P450 based

e.g. UGTs

Biliary

(active & passive)

Distribution

Blood-Brain Barrier Plasma protein binding Volume of distributionTransporters

Absorption

Phys.chem properties

e.g. Predicted LogP

HIA- Passive

Absorption

GI Metabolism by

CYP3A4

Transporters

e.g. Pgp

Oral dose

Solubility pH stability

P450 Inhibi tion and inductionReactive Intermediate Formation


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The Bucket

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Although pharmacokineticshas a complex origin,

most important concepts canbe explained with a bucket.


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Is pharmacokinetics important?| Critical component of preclinical and clinical

drug development programsz Regulatory necessity that hopefully leads to

rational design of drug dosing regimens

| Integral component of experimentaltherapeutics research

z PK/PD, pharmacogenetics/polymorphisms,drug delivery to tissues, targetedtherapeutics

| Clinical PK/PD; drug dosage design,individualized regimens based on covariates

|

PK information is a stalwart of a pharmacistsexpertise


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Pharmacokinetics in Drug

Discovery and Development

CandidateSelection EarlyDevelopment FIM POCLead Optimization LateDevelopment

Predicting human PK

from in vitro dataMeasuring human PK

= Compound synthesis

= Compound testing

Population PKPredicting human PK

from animal data


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ADME Properties

Hepatic clearance

P450 Metabolism: CYP3A4

Regioselectivity/Lability

Non-P450 based

e.g. UGTs

Biliary

(active & passive)

Distribution

Blood-Brain Barrier Plasma protein binding Volume of distributionTransporters

Absorption

Phys.chem properties

e.g. Predicted LogP

HIA- Passive

Absorption

GI Metabolism by

CYP3A4

Transporters

e.g. Pgp

Oral dose

Solubility pH stability

P450 Inhibi tion and inductionReactive Intermediate Formation


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Is Pharmacokinetics

Important?

Failures due to unfavorable PK properties (poor bioavailability,rapid clearance, etc.) have been decreased due to betterexperiments and interpretation.

Ref - Peter Van Osta, MD, 2010


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Essence of Clinical PK - Design of

Drug Dosing Regimens


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Pharmacokinetic Variability

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| Designing optimum therapeutic regimensz Understanding variability due to:

z Age (pediatric, adult, elderly)

z Genetic variationz Dietz Drug-drug interactions

i id f h


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Dosing outside of the

Therapeutic Window

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| Under-dosingz Resistance antimicrobialsz Pregnancy birth control pills

z Pain analgesicsz Stroke anticoagulantsz Etc.

z Overdosing

z Any number of toxicitiesz Death


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Gentamicin dosing in neonates

Elevated peak (>12 mg/L) can cause ototoxicityElevated trough (>1 mg/L) can cause nephrotoxicity

Table 1. Weight-Based, Extended-Interval Gentamicin

Dosing Protocol

Birth Weight Protocol< 1250 g 4 mg/kg i.v. q48h

1250 g + indomethacin 4 mg/kg i.v. q48h

1250 g 4 mg/kg i.v. q24h

Z O d Eli i ti


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Zero-Order Elimination

Kinetics

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| Question: When consuming alcohol, why do things go so

bad so quickly?

z Answer: Zero-order elimination kineticsz Most drugs are eliminated faster at higher drug

concentrationsz Alcohol metabolism is quickly saturated, resulting in

zero-order kinetics. Consumption at rates greater thanelimination results in rapid and continuous increases inalcohol levels.

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Pharmac Kinetics