title: Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients.
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 [AUC0-24]) were higher in SP than in BP (median AUC0-24, 7.01 versus 2.97 mg · liter-1· h, respectively). The median (range) SP-to-BP AUC0-24ratio 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 AUC0-24or TFV SP-to-BP AUC0-24ratio 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.
authors.affiliation: Université Paris Descartes, EA7323, Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique Paris Descartes Necker Cochin, Assistance Publique des Hôpitaux de Paris, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Valade
authors.affiliation: Université Paris Descartes, EA7323, Sorbonne Paris Cité, Paris, France naim.bouazza@aphp.fr.|Unité de Recherche Clinique Paris Descartes Necker Cochin, Assistance Publique des Hôpitaux de Paris, Paris, France.|CIC-1419 INSERM, Cochin-Necker, Paris, France.
authors.forename: Naïm
authors.initials: N
authors.lastname: Bouazza
authors.affiliation: Université Paris Descartes, EA7323, Sorbonne Paris Cité, Paris, France.|Service de Pharmacologie Clinique, Hôpital Cochin, Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Paris Centre, Paris, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Lui
authors.affiliation: Université Paris Descartes, EA7323, Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique Paris Descartes Necker Cochin, Assistance Publique des Hôpitaux de Paris, Paris, France.|CIC-1419 INSERM, Cochin-Necker, Paris, France.|Service de Pharmacologie Clinique, Hôpital Cochin, Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Paris Centre, Paris, France.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Illamola
authors.affiliation: Université Paris Descartes, EA7323, Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique Paris Descartes Necker Cochin, Assistance Publique des Hôpitaux de Paris, Paris, France.|CIC-1419 INSERM, Cochin-Necker, Paris, France.|Service de Pharmacologie Clinique, Hôpital Cochin, Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Paris Centre, Paris, France.
authors.forename: Sihem
authors.initials: S
authors.lastname: Benaboud
authors.affiliation: Université Paris Descartes, EA7323, Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique Paris Descartes Necker Cochin, Assistance Publique des Hôpitaux de Paris, Paris, France.|CIC-1419 INSERM, Cochin-Necker, Paris, France.|Service de Pharmacologie Clinique, Hôpital Cochin, Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Paris Centre, Paris, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Treluyer
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cobat
authors.affiliation: Université Paris Descartes, EA7323, Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique Paris Descartes Necker Cochin, Assistance Publique des Hôpitaux de Paris, Paris, France.|CIC-1419 INSERM, Cochin-Necker, Paris, France.
authors.forename: Frantz
authors.initials: F
authors.lastname: Foissac
authors.affiliation: Université Paris Descartes, EA7323, Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique Paris Descartes Necker Cochin, Assistance Publique des Hôpitaux de Paris, Paris, France.
authors.forename: Maïlys
authors.initials: M
authors.lastname: De Sousa Mendes
authors.affiliation: Service de Diagnostic Biologique Automatisé, Hôpital Cochin, Hopitaux Universitaires Paris Centre, Assistance Publique des Hôpitaux de Paris, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Chenevier-Gobeaux
authors.affiliation: Aix Marseille Université, INSERM, IRD, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Marseille, France.|UMR_S912, IRD, Aix Marseille Université, Marseille, France.|Observatoire Régional de la Santé Provence-Alpes-Côte d'Azur, Marseille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Suzan-Monti
authors.affiliation: Université Paris Descartes, EA 7327, Sorbonne Paris Cité, Paris, France.|Laboratoire de Virologie, Centre Hospitalier Universitaire Necker Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Rouzioux
authors.affiliation: INSERM, UMR-S 943, Université Pierre et Marie Curie, Paris, France.
authors.forename: Lambert
authors.initials: L
authors.lastname: Assoumou
authors.affiliation: Université Paris Descartes, EA 7327, Sorbonne Paris Cité, Paris, France.|Assistance Publique des Hôpitaux de Paris, Unité Fonctionnelle de Thérapeutique en Immuno-Infectiologie, Hôpitaux Universitaires Paris Centre Site Hôtel Dieu, Paris, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Viard
authors.affiliation: Université Paris Descartes, EA7323, Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique Paris Descartes Necker Cochin, Assistance Publique des Hôpitaux de Paris, Paris, France.|CIC-1419 INSERM, Cochin-Necker, Paris, France.
authors.forename: Saïk
authors.initials: S
authors.lastname: Urien
authors.affiliation: Université Paris Descartes, EA 7327, Sorbonne Paris Cité, Paris, France.|Assistance Publique des Hôpitaux de Paris, Unité Fonctionnelle de Thérapeutique en Immuno-Infectiologie, Hôpitaux Universitaires Paris Centre Site Hôtel Dieu, Paris, France.
authors.forename: Jade
authors.initials: J
authors.lastname: Ghosn
authors.affiliation: Université Paris Descartes, EA7323, Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique Paris Descartes Necker Cochin, Assistance Publique des Hôpitaux de Paris, Paris, France.|CIC-1419 INSERM, Cochin-Necker, Paris, France.|Service de Pharmacologie Clinique, Hôpital Cochin, Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Paris Centre, Paris, France.
authors.forename: Déborah
authors.initials: D
authors.lastname: Hirt
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001499:Bayes Theorem; D001682:Biological Availability; D001835:Body Weight; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D015870:Gene Expression; D005837:Genitalia, Male / Q000737:chemistry / Q000187:drug effects* / Q000821:virology; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006801:Humans; D008297:Male; D008390:Markov Chains; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D015233:Models, Statistical; D009010:Monte Carlo Method; D020641:Polymorphism, Single Nucleotide; D012661:Semen / Q000737:chemistry / Q000187:drug effects / Q000821:virology; D000068698:Tenofovir / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D000068698:Tenofovir; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: genital tract; population pharmacokinetics; seminal plasma; tenofovir