PHARMACOKINETIC DRUG

ENHANCEMENT
Learning Objectives
Overview of Pharmacokinetics Drug
Interaction

Pharmacokinetic Drug Enhancement

Rationale
and importance of
pharmacokinetic enhancement
Overview of Pharmacokinetics
Drug Interaction
Pharmacokinetic Drug Interaction: is the
interaction of drugs during
 Absorption
 distribution within body

Metabolism
 drug elimination
Drug Metabolizing Enzymes
 Liver: major organ for drug metabolism
 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. hydroxylations
Proportions of CYP450 Enzymes In Human Liver

CYP450 Known Drugs Metabolized

CYP1A2 4%

CYP2C9 10%

CYP2C19 2%

CYP2D6 30%

CYP3A4 50%
 Metabolic Drug Interactions

 Inhibition Enz. Activity Drug Conc.

 Induction
Enz. Activity Drug Conc.
Pharmacokinetic (PK) enhancement
Pharmacokinetic (PK) enhancement is the
concept of combining agents to improve
ARV pharmacokinetics.
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 PI
DRUGS
 PI therapy for HIV infection is typically associated with
administration of multiple oral doses at frequent
intervals throughout the day.
Importance:
 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
 Pharmacokinetics Principles
10
Cmax
maximum concentration
8 correlates with some short-term side
effects, e.g. nausea
Concentration (ug/mL)

AUC
4 area under the curve
overall drug exposure

0
2 4 6 8 10 12 9
 Pharmacokinetics Principles (2)
10
Cmin
minimum, or trough concentration
8 occurs at the end of the dosing interval
Concentration (ug/mL)

correlates with anti-HIV effect for all PIs

0
2 4 6 8 10 12
10
Pharmacokinetic Effects of Ritonavir on
Other PIs
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 trough concentrations
and may also raise peak concentrations (
Figure 1).
Pharmacokinetic Effects …
Pharmacokinetic Effects …
Ritonavir used to “boost” 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 Points
Pharmacokinetic enhancement is a
combination of drugs that helps:
◦ Improve ARV pharmacokinetics
◦ Improve adherence
◦ Minimize side effects
◦ Enhance antiviral activity and prevent
resistance
Pharmacokinetic Effects …
Ritonavir (cont)
◦ Overcomes enzyme induction caused by other
drugs
◦ Increase drug exposure
◦ Remove meal requirements