Influence of pharmacogenetics on indinavir disposition and short-term response in HIV patients initiating HAART
| Autor: | Julie, Bertrand, Jean-Marc, Treluyer, Xavière, Panhard, Agnes, Tran, Solange, Auleley, Elisabeth, Rey, Dominique, Salmon-Céron, Xavier, Duval, France, Mentré, X, Panhard |
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| Přispěvatelé: | Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques (U738 / UMR_S738), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, Université Paris Descartes - Paris 5 (UPD5), Service de Pharmacologie Clinique, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UF de Biostatistiques, Université Paris Diderot - Paris 7 (UPD7), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Centre d'Investigation Clinique, Hôpital Bichat, AP-HP, Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), CHU Cochin [AP-HP], Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Département d'épidémiologie, biostatistique et recherche clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Agence de Recherche Nationale sur le SIDA (ANRS, Essai 111) for financial support. During this analysis J. Bertrand was supported by a grant from Servier Research Group, France., Cophar2-ANRS 111 Study Group, Université Paris Diderot - Paris 7 (UPD7) - Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [AP-HP] - Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) - AP-HP - Hôpital Bichat - Claude Bernard [Paris], CHU Cochin [AP-HP] - Assistance publique - Hôpitaux de Paris (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Comets, Emmanuelle |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
MESH : Prospective Studies MESH : Genotype HIV Infections Indinavir Pharmacology MESH: Genotype 0302 clinical medicine MESH : Cytochrome P-450 CYP3A Multicenter Studies as Topic Pharmacology (medical) Prospective Studies MESH: Anti-HIV Agents ComputingMilieux_MISCELLANEOUS MESH: Treatment Outcome Volume of distribution 0303 health sciences education.field_of_study MESH: Middle Aged MESH : Pilot Projects MESH : HIV Protease Inhibitors virus diseases General Medicine MESH: HIV Infections [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] 3. Good health Area Under Curve Safety Genotype Efficacy Metabolic Clearance Rate MESH: Pharmacogenetics MESH : Cohort Studies Article 03 medical and health sciences Pharmacokinetics MESH: Polymorphism Genetic MESH : HIV Infections Humans MESH : Middle Aged education Models Statistical Polymorphism Genetic MESH: Humans MESH: Indinavir MESH : Humans MESH: Adult Protease inhibitors MESH : Antiretroviral Therapy Highly Active MESH: Pilot Projects Bioavailability MESH : Clinical Trials as Topic Pharmacogenetics HIV-1 MESH: Multicenter Studies as Topic [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] MESH: Female MESH: Models Statistical CYP3A4 MESH : Polymorphism Genetic Pilot Projects 030226 pharmacology & pharmacy MESH : Multicenter Studies as Topic MESH: Antiretroviral Therapy Highly Active Cohort Studies MESH: HIV-1 MESH : Metabolic Clearance Rate Nonlinear mixed effects modeling Antiretroviral Therapy Highly Active Cytochrome P-450 CYP3A MESH : Female MESH: Cohort Studies [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM] MESH: Cytochrome P-450 CYP3A Clinical Trials as Topic [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] MESH : Models Statistical MESH : Adult Middle Aged Treatment Outcome Female MESH : Pharmacogenetics MESH : HIV-1 medicine.drug Adult Pharmacokinetics · Nonlinear Mixed Effects Modeling · Protease inhibitors · CYP3A4 · Safety · Efficacy MESH: Clinical Trials as Topic Anti-HIV Agents MESH : Male Population Cmax MESH : Treatment Outcome Biology medicine MESH : Indinavir 030304 developmental biology MESH: HIV Protease Inhibitors MESH: Metabolic Clearance Rate MESH : Anti-HIV Agents HIV Protease Inhibitors MESH: Male MESH: Prospective Studies MESH: Area Under Curve Ritonavir MESH : Area Under Curve |
| Zdroj: | European Journal of Clinical Pharmacology European Journal of Clinical Pharmacology, Springer Verlag, 2009, 65 (7), pp.667-678. ⟨10.1007/s00228-009-0660-5⟩ European Journal of Clinical Pharmacology, Springer Verlag, 2009, 65 (7), pp.667-678. 〈10.1007/s00228-009-0660-5〉 European Journal of Clinical Pharmacology, Springer Verlag, 2009, 65 (7), pp.667-78. ⟨10.1007/s00228-009-0660-5⟩ European Journal of Clinical Pharmacology, Springer Verlag, 2009, 65 (7), pp.667-78. 〈10.1007/s00228-009-0660-5〉 |
| ISSN: | 0031-6970 1432-1041 |
| DOI: | 10.1007/s00228-009-0660-5⟩ |
| Popis: | International audience; AIMS: To assess the relationship between genetic polymorphisms and indinavir pharmacokinetic variability and to study the link between concentrations and short-term response or metabolic safety. METHODS: Forty protease inhibitor-naive patients initiating highly active antiretroviral therapy (HAART) including indinavir/ritonavir and enrolled in the COPHAR 2-ANRS 111 trial were studied. At week 2, four blood samples were taken before and up to 6 h following drug intake. A population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization (SAEM) algorithm implemented in MONOLIX software. The area under the concentration-time curve (AUC) and maximum (C(max)) and trough concentrations (C(trough)) of indinavir were derived from the population model and tested for their correlation with short-term viral response and safety measurements, while for ritonavir, these same three parameters were tested for their correlation with short-term biochemical safety RESULTS: A one-compartment model with first-order absorption and elimination best described both indinavir and ritonavir concentrations. For indinavir, the estimated clearance and volume of distribution were 22.2 L/h and 97.3 L, respectively. The eight patients with the *1B/*1B genotype for the CYP3A4 gene showed a 70% decrease in absorption compared to those with the *1A/*1B or *1A/*1A genotypes (0.5 vs. 2.1, P = 0.04, likelihood ratio test by permutation). The indinavir AUC and C(trough) were positively correlated with the decrease in human immunodeficiency virus RNA between week 0 and week 2 (r = 0.4, P = 0.03 and r = -0.4, P = 0.03, respectively). Patients with the *1B/*1B genotype also had a significantly lower indinavir C(max) (median 3.6, range 2.1-5.2 ng/mL) than those with the *1A/*1B or *1A/*1A genotypes (median 4.4, range 2.2-8.3 ng/mL) (P = 0.04) and a lower increase in triglycerides during the first 4 weeks of treatment (median 0.1, range -0.7 to 1.4 vs. median 0.6, range -0.5 to 1.7 mmol/L, respectively; P = 0.02). For ritonavir, the estimated clearance and volume of distribution were 8.3 L/h and 60.7 L, respectively, and concentrations were not found to be correlated to biochemical safety. Indinavir and ritonavir absorption rate constants were found to be correlated, as well as their apparent volumes of distribution and clearances, indicating correlated bioavailability of the two drugs. CONCLUSION: The CYP3A4*1B polymorphism was found to influence the pharmacokinetics of indinavir and, to some extent, the biochemical safety of indinavir. |
| Databáze: | OpenAIRE |
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