Effect of adherence as measured by MEMS, ritonavir boosting, and CYP3A5 genotype on atazanavir pharmacokinetics in treatment-naive HIV-infected patients.

Radojka Savic 1, 2 Aurélie Barrail-Tran 3, 4 Xavier Duval 1 George Nembot 1 Xavière Panhard 1 Diane Descamps 5 Céline Verstuyft 6 Bernard Vrijens 7 Anne-Marie Taburet 3 Cécile Goujard 8 France Mentré 9, *
* Auteur correspondant
1 Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques
2 Department of Bioengineering and Therapeutic Sciences
3 Service de pharmacie
4 Faculté de Pharmacie
5 Laboratoire de Virologie
6 Service de génétique moléculaire, pharmacogénétique et hormonologie
7 AARDEX Group
8 Service de médecine interne et maladies infectieuses
9 UMR 738
Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques
Abstract : We investigated population pharmacokinetics and pharmacogenetics of ritonavir-boosted atazanavir (ATV), using drug intake times exactly recorded by the Medication Event Monitoring System. The ANRS 134-COPHAR 3 trial was conducted in 35 HIV-infected treatment-naive patients. ATV (300 mg), ritonavir (100 mg), and tenofovir (300 mg) + emtricitabine (200 mg), in bottles with MEMS caps, were taken once daily for 6 months. Six blood samples were collected at week 4 to measure drug concentrations, and trough levels were measured bimonthly. A model integrating ATV and ritonavir pharmacokinetics and pharmacogenetics used nonlinear mixed effects. Use of exact dosing data halved unexplained variability in ATV clearance. The ritonavir-ATV interaction model suggested that optimal boosting effect is achievable at lower ritonavir exposures. Patients with at least one copy of the CYP3A5*1 allele exhibited 28% higher oral clearance. We provide evidence that variability in ATV pharmacokinetics is defined by adherence, CYP3A5 genotype, and ritonavir exposure.
Keywords : Atazanavir Adherence Pharmacogenetics Population pharmacokinetics
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Article dans une revue
Clinical Pharmacology and Therapeutics, American Society for Clinical Pharmacology and Therapeutics, 2012, 92 (5), pp.575-83. 〈10.1038/clpt.2012.137〉
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Radojka Savic, Aurélie Barrail-Tran, Xavier Duval, George Nembot, Xavière Panhard, et al.. Effect of adherence as measured by MEMS, ritonavir boosting, and CYP3A5 genotype on atazanavir pharmacokinetics in treatment-naive HIV-infected patients.. Clinical Pharmacology and Therapeutics, American Society for Clinical Pharmacology and Therapeutics, 2012, 92 (5), pp.575-83. 〈10.1038/clpt.2012.137〉. 〈inserm-00747884〉

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