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. 2007 Sep;64(3):353-62.
doi: 10.1111/j.1365-2125.2007.02903.x. Epub 2007 May 22.

Minimal effect of MDR1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of indinavir in HIV-infected patients

Caroline Solas  1 , Nicolas Simon, Marie-Pierre Drogoul, Sylvie Quaranta, Véronique Frixon-Marin, Véronique Bourgarel-Rey, Corinne Brunet, Jean-Albert Gastaut, Alain Durand, Bruno Lacarelle, Isabelle Poizot-Martin
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Minimal effect of MDR1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of indinavir in HIV-infected patients

Caroline Solas et al. Br J Clin Pharmacol. 2007 Sep.

Abstract

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 by MDR1. Using a population pharmacokinetic approach, we investigated the effect of several MDR1 and CYP3A5 polymorphisms 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 for MDR1 and by PCR-SSCP analysis for CYP3A5.

Results: The pharmacokinetics of indinavir were best described by a one-compartment model with first-order absorption. In the final model, the MDR1 C3435T 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 the CYP3A5*3/*3 genotype receiving indinavir alone had a 31% decrease in the indinavir clearance rate compared with patients carrying the CYP3A5*1/*3 genotype.

Conclusions: The MDR1 C3435T 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, genotyping MDR1 and/or CYP3A5 to optimize protease inhibitor boosted regimens does not seem clinically relevant.

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Figures

Figure 1
Figure 1
Observed indinavir plasma concentration vs. time profiles of HIV-infected patients (A) without RTV and (B) with RTV 100 mg twice daily. Indinavir concentrations were log-transformed. IDV = indinavir
See this image and copyright information in PMC

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