1. Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients
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Saïk Urien, Déborah Hirt, Marie Suzan-Monti, Jade Ghosn, Christine Rouzioux, Elodie Valade, Lambert Assoumou, Sílvia M. Illamola, Frantz Foissac, Jean-Marc Tréluyer, Maïlys De Sousa Mendes, Sihem Benaboud, Gabrielle Lui, Naïm Bouazza, Jean-Paul Viard, Aurélie Cobat, Camille Chenevier-Gobeaux, Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de Pharmacologie Clinique [CHU Cochin], Hôpital Cochin [AP-HP], CTG repeat instability and myotonic dystrophy (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Observatoire régional de la santé Provence-Alpes-Côte d'Azur [Marseille] (ORS PACA), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Infection à VIH, réservoirs, diversité génétique et résistance aux antirétroviraux (ARV) (EA 7327), Laboratoire de Virologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM), UF de Thérapeutique en Immuno‑Infectiologie [AP-HP Hôtel Dieu], Hôpital Hôtel-Dieu [Paris], Service de médecine interne et maladies infectieuses, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, The French National Agency for Research on AIDS and Viral Hepatitis (ANRS) sponsored the Evarist study. This study also received financial support from SIDACTION., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Lissalde, Claire
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0301 basic medicine ,Male ,Physiology ,Gene Expression ,HIV Infections ,population pharmacokinetics ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Blood plasma ,Medicine ,Pharmacology (medical) ,Drug Dosage Calculations ,education.field_of_study ,Liter ,Middle Aged ,HIV Reverse Transcriptase ,Markov Chains ,Infectious Diseases ,Area Under Curve ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Monte Carlo Method ,medicine.drug ,Adult ,Tenofovir ,Anti-HIV Agents ,Population ,Biological Availability ,Single-nucleotide polymorphism ,Semen ,Microbial Sensitivity Tests ,Genitalia, Male ,Polymorphism, Single Nucleotide ,Drug Administration Schedule ,03 medical and health sciences ,Pharmacokinetics ,Humans ,education ,Pharmacology ,Models, Statistical ,business.industry ,Body Weight ,Bayes Theorem ,genital tract ,030112 virology ,tenofovir ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,HIV-1 ,seminal plasma ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,business ,Pharmacogenetics - Abstract
The aims of this study were to describe the blood plasma (BP) and seminal 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 pharmacogenetic assessment, a total of 121 single nucleotide polymorphisms (SNP) were genotyped. 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.
- Published
- 2017
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