Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients

Elodie Valade 1 Naim Bouazza 1, 2, * Gabrielle Lui 3, 4 Silvia Illamola 1, 2, 4 Sihem Benaboud 1, 2, 4 Jean-Marc Tréluyer 1, 2, 4 Aurélie Cobat 5 Frantz Foissac 1, 2 Maïlys de Sousa Mendes 1 Camille Chenevier-Gobeaux 6 Marie Suzan-Monti 7, 8 Christine Rouzioux 9, 10, 11 Lambert Assoumou 12 Jean-Paul Viard 13, 10 Saik Urien 2, 1 Jade Ghosn 14, 13, 10 Déborah Hirt 15, 1, 2, 4
Abstract : The aims of this study were to describe the blood plasma (BP) and semi-nal plasma (SP) pharmacokinetics of tenofovir (TFV) in HIV-1-infected men, to assess the role of genetic polymorphism in the variability of TFV transfer into the male genital tract, and to evaluate the impact of TFV SP exposure on seminal plasma HIV load (spVL). Men from the Evarist-ANRS EP 49 study treated with TFV as part of their antiretroviral therapy were included in the study. A total of 248 and 217 TFV BP and SP concentrations from 129 men were available for the analysis. For pharmacoge-netic assessment, a total of 121 single nucleotide polymorphisms (SNP) were geno-typed. Data were analyzed using a nonlinear mixed-effects modeling approach. TFV pharmacokinetics were best described by a two-compartment model for BP and by an effect compartment with different input and output constants for SP. TFV exposures (area under the concentration-time curve from 0 to 24 h [AUC 0-24 ]) were higher in SP than in BP (median AUC 0-24 , 7.01 versus 2.97 mg · liter 1 · h, respectively). The median (range) SP-to-BP AUC 0-24 ratio was 2.24 (0.53 to 34.13). After correction for multiple testing, none of the SNPs were significantly associated with the TFV transfer rate constant. The impact of the TFV SP AUC 0-24 or TFV SP-to-BP AUC 0-24 ratio on spVL was not significant (P 0.808 and 0.768, respectively). This is the first population model describing TFV pharmacokinetics in the male genital tract. TFV SP concentrations were higher than BP concentrations. Despite TFV SP exposures being higher than BP exposures, an spVL was detectable for 12.2% of the men.
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Soumis le : vendredi 18 janvier 2019 - 19:14:17
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Elodie Valade, Naim Bouazza, Gabrielle Lui, Silvia Illamola, Sihem Benaboud, et al.. Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients. Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2017, 61 (3), pp.e02062-16. ⟨10.1128/aac.02062-16⟩. ⟨inserm-01986570⟩



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