Minimal effect of MDR1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of indinavir in HIV‐infected patients
Authors: Solas Caroline , Simon Nicolas , Drogoul Marie‐Pierre , Quaranta Sylvie , Frixon‐Marin Véronique , Bourgarel‐Rey Véronique , Brunet Corinne , Gastaut Jean‐Albert , Durand Alain , Lacarelle Bruno , Poizot‐Martin Isabelle 
Published: May 2007

What is already known about this subject

• Before this study, few data were available on the potential effect of genetic variants of P‐glycoprotein or the CYP3A5 enzyme on the pharmacokinetic variability of protease inhibitors (PI).

• MDR1C3435T polymorphism was often linked with the pharmacokinetic variability of nelfinavir.CYP3A5*3polymorphism was linked with the pharmacokinetic variability of calcineurin inhibitors and was therefore strongly suspected of being one of the key factors in the pharmacokinetic variability of other CYP3A susbtrates.

What this study adds

• Our results showed that bothMDR1C3435T andCYP3A5*3polymorphisms are involved in the pharmacokinetic variability of the absorption or elimination of indinavir, but probably jointly with other factors.

• The potent CYP3A inhibitory effect of ritonavir may hide the variability linked to genetic differences in theCYP3A5gene, thereby reducing the overall pharmacokinetic variability of the boosted protease inhibitor.

• GenotypingMDR1and/orCYP3A5does not appear to be a clinically relevant factor in optimizing protease inhibitor boosted regimens.

Aims

The protease inhibitor indinavir is characterized by an important interindividual pharmacokinetic variability, which results from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A and the multidrug efflux pump P‐glycoprotein (P‐gp), encoded byMDR1. Using a population pharmacokinetic approach, we investigated the effect of severalMDR1andCYP3A5polymorphisms on the pharmacokinetic parameters of indinavir in HIV‐infected patients.

Methods

Twenty‐eight patients receiving indinavir alone or together with ritonavir were included. Indinavir pharmacokinetics were studied over a 12 h interval. Genetic polymorphisms were assessed by real‐time PCR assays and direct sequencing forMDR1and by PCR‐SSCP analysis forCYP3A5.

Results

The pharmacokinetics of indinavir were best described by a one‐compartment model with first‐order absorption. In the final model, theMDR1C3435T genotype and ritonavir were identified as statistically significant covariates (P ≤ 0.001) for the absorption rate constant (95% confidence interval on the difference between CC and CT genotype 0.37, 5.53) and for clearance (95% confidence interval on the difference 5.8, 26.2), respectively. Patients with theCYP3A5*3/*3genotype receiving indinavir alone had a 31% decrease in the indinavir clearance rate compared with patients carrying theCYP3A5*1/*3genotype.

Conclusions

TheMDR1C3435T genotype affects the absorption constant of indinavir suggesting that P‐gp may be implicated in its pharmacokinetic variability. Through its inhibition of CYP3A and P‐gp, ritonavir could attenuate the pharmacokinetic variability linked to genetic differences, reducing significantly the interindividual variability of indinavir. However, genotypingMDR1and/orCYP3A5to optimize protease inhibitor boosted regimens does not seem clinically relevant.