Pharmacokinetic Model of Tenofovir and Emtricitabine and Their Intracellular Metabolites in Patients in the ANRS 134-COPHAR 3 Trial Using Dose Records.

•• Palmer Palmer,•• Brunet Brunet,•• Peytavin Peytavin,•• Nau Nau,•• Delhotal Delhotal,•• Chaix Chaix,•• Ciuchete Ciuchete,•• Storto Storto,•• Molina Molina,•• Marien Marien,•• Thoirain Thoirain,•• Thanh Thuy Thanh Thuy,Cécile Goujard,•• Taburet Taburet,•• Kouadio Kouadio,•• Soulié Soulié,•• Calvez Calvez,•• Poinçon De La Blanchardière Poinçon De La Blanchardière,Aurélie Barrail-Tran,Céline Verstuyft,M.-J Commoy,•• Deschamps Deschamps,•• Lupin Lupin,•• Rami Rami,•• Bolmann Bolmann,•• Baclet Baclet,•• Sellier Sellier,•• Boulanger Boulanger,France Mentré,•• Mole Mole,•• Barrail-Tran Barrail-Tran,•• Metivier Metivier,Anne‐Marie Taburet ,•• Mourez Mourez,•• Goujard Goujard,Delphyne Descamps ,•• Morand-Joubert Morand-Joubert,•• Ouazene Ouazene,•• Parienti Parienti,•• Gaubin Gaubin,Guillemette Unal ,•• Brochier Brochier,S Couffin-Cadiergues,•• Quertainmont Quertainmont,•• Sauvageon Sauvageon,•• Ferret Ferret,Xavier Duval ,Elina Teicher,Xavière Panhard ,•• Wassoumbou Wassoumbou,•• Talbi Talbi,•• Duval Duval,•• Trépo Trépo,•• Bocket Bocket,•• Simon Simon,•• Poirier Poirier,•• Parrinello Parrinello,Caroline Barau,•• Ghosn Ghosn,•• Houdret Houdret,•• Bollens Bollens,•• Yazdanpanah Yazdanpanah,•• Hoizey Hoizey,Alain Pruvost,•• Mazeron Mazeron,•• André André,Bernard Vrijens ,•• May May,•• Harchi Harchi,•• Medintzeff Medintzeff,Chantal Le Guellec ,Julie Bertrand,•• Pintado Pintado,•• Besnier Besnier,Lucie Fayette,Georges Nembot ,•• Ajana Ajana,Radojka M Savic ,•• Ramani Ramani,•• Leguellec Leguellec,A Brunet,•• Verdon Verdon,•• Aissi Aissi,•• Gagneux Gagneux,•• Girard Girard,•• Pallier Pallier

doi:10.1128/aac.02339-18

Abstract

Tenofovir (TFV) and emtricitabine (FTC) are part of the recommended highly active antiretroviral therapy (ART). Both molecules show a large interindividual pharmacokinetic (PK) variability. Here, we modeled the concentrations of plasma TFV and FTC and their intracellular metabolites (TFV diphosphate [TFV-DP] and FTC triphosphate [FTC-TP]) collected after 4 and 24 weeks of treatment in 34 patients from the ANRS 134-COPHAR 3 trial. These patients received daily (QD) atazanavir (300 mg), ritonavir (100 mg), and a fixed-dose combination of coformulated TFV disoproxil fumarate (300 mg) and FTC (200 mg). Dosing history was collected using a medication event monitoring system. A three-compartment model with absorption delay (Tlag) was selected to describe the PK of, respectively, TFV/TFV-DP and FTC/FTC-TP. TFV and FTC apparent clearances, 114 L/h (relative standard error [RSE] = 8%) and 18.1 L/h (RSE = 5%), respectively, were found to decrease with age. However, no significant association was found with the polymorphisms ABCC2 rs717620, ABCC4 rs1751034, and ABCB1 rs1045642. The model allows prediction of TFV-DP and FTC-TP concentrations at steady state with alternative regimens.

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