pharmacokinetic drug enhancement

8/7/2019 Pharmacokinetic Drug Enhancement

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PHARMACOKINETIC DRUG

ENHANCEMENT



Learning ObjectivesLearning Objectives

y Overview of Pharmacokinetics Drug

Interaction

y Pharmacokinetic Drug Enhancement

y Rationale and importance of

pharmacokinetic enhancement



Overview of PharmacokineticsOverview of Pharmacokinetics

Drug InteractionDrug Interactiony Pharmacokinetic Drug Interaction: is the

interaction of drugs during

Absorption

distribution within body

Metabolism

drug elimination



Drug Metabolizing EnzymesDrug Metabolizing Enzymes

y Liver: major organ for drug metabolism

y Phase I and Phase II Enzymes

Phase I: oxidative or hydrolytic reactions

Phase II: conjugative reactions

� Predominate enzyme : cytochrome P450 (CYP450)

mediate oxidation reactions, eg. hydroxylationsProportions of CYP450 Enzymes In Human Liver

CYP450 Known Drugs Metabolized

CYP1A2 4%

CYP2C9 10%

CYP2C19 2%

CYP2D6 30%

CYP3A4 50%



Metabolic Drug InteractionsMetabolic Drug Interactions

y Inhibition

y Induction

Enz. Activity

Enz. Activity

Drug Conc.

Drug Conc.



Pharmacokinetic (PK) enhancementPharmacokinetic (PK) enhancement

y Pharmacokinetic (PK) enhancement is the

concept of combining agents to improve

ARV pharmacokinetics.

y PK enhancement takes advantage of

enzyme inhibiting properties in order to

improve the PK profile and/or

bioavailability of one or more drugs.



RATIONALE FOR PK ENHANCEMENT OF PIRATIONALE FOR PK ENHANCEMENT OF PI

DRUGSDRUGS

y PI therapy for HIV infection is typically associated with

administration of multiple oral doses at frequent

intervals throughout the day.

Importance:

y Coadministration of low doses of the PI ritonavir, in

conjunction with therapeutic doses of one or more PIs,

is used to enhance, or boost, the pharmacologic effects

of the concomitant PIs.

simpler dosing schedules improve adherence

lower pill volume and to anti-HIV therapy

less frequent administration



9

Pharmacokinetics PrinciplesPharmacokinetics Principles

0

2

4

6

8

10

Concentration (ug/m

L)

2 4 10 126 8

Cmax

maximum concentration

correlates with some short-term side

effects, e.g. nausea

AUC

area under the curve

overall drug exposure



10

Pharmacokinetics Principles (2)Pharmacokinetics Principles (2)

0

2

4

6

8

10

Concentration (ug/mL)

2 4 10 126 8

Cmin

minimum, or trough concentration

occurs at the end of the dosing interval

correlates with anti-HIV effect for all PIs



Pharmacokinetic Eff ects of Pharmacokinetic Eff ects of Ritonavir Ritonavir

on Other PIson Other PIs

y Ritonavir

most common compound used in clinical

practice to boost the antiviral activity of PIs

for the treatment of HIV infection. Its inhibitory effects on CYP450 (3A4) and

P-glycoprotein can increase the extent of

absorption and slow the clearance of the

primary PI. raises plasma troughconcentrations and may also raise peak

concentrations (Figure 1).



Pharmacokinetic Eff ects «Pharmacokinetic Eff ects «




y Ritonavir used to ́ boostµ Cmin and

increase t½ of other protease inhibitors

Allows extended dosing intervals

Decreases pill burden

Reduces adverse effects

May allow salvage in patients with resistance

and reduced susceptibility



Key PointsKey Points

y Pharmacokinetic enhancement is acombination of drugs that helps: ImproveARV pharmacokinetics

Improve adherence

Minimize side effects

Enhance antiviral activity and preventresistance




y Ritonavir (cont)

Overcomes enzyme induction caused by

other drugs

Increase drug exposure

Remove meal requirements

pharmacokinetic drug enhancement

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