Joint pharmacogenetic model of tenofovir and emtricitabine and their active intracellular metabolites in HIV Patients
Julie Bertrand (1), Aurélie Barrail-Tran (2), Rada Savic (3), Céline Verstuyft (4) and the ANRS 134 COPHAR3 trial group
(1) UMR 1137 IAME INSERM Université Paris Diderot, (2) AP-HP, Hôpital Bicêtre, Pharmacie Clinique ; Université Paris Sud ; INSERM UMR 1184, Center for Immunology of Viral Infections and Autoimmune Diseases (3) Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, (4) Service de génétique moléculaire et pharmacogénétique, hôpital Bicêtre, AP-HP; Université Paris Sud; INSERM UMR 1184, Center for Immunology of Viral Infections and Autoimmune Diseases
Context: According to the 2016 NIH guidelines, tenofovir (TFV) and emtricitabine (FTC) are part of the recommended antiretroviral therapy (ART) regimen for naïve HIV patients and since 2012, the WHO recommends offering oral PrEP containing TFV. Several pharmacokinetic (PK) and some PK/pharmacodynamic models have been proposed for both molecules leading to identification of target concentrations for their active intracellular metabolites (TFV-DP and FTC-TP, respectively) [1, 2]. However the large inter-individual variability in TFV, TFV-DP, FTC and FTC-TP PK parameters is so far unexplained.
Objectives: To perform a joint population pharmacogenetic analysis of TFV, TFV-DP, FTC and FTC-TP concentrations and genetic variants collected in the ANRS 134 COPHAR3 trial.
Methods: The trial included 35 HIV naïve patients on an atazanavir/ritonavir/TFV/FTC treatment in MEMS-capped bottles. Plasma TFV and FTC concentrations were measured at W4 (pre and 1, 2, 3, 4, and 8 h after the dose) and at W24 (trough) with trough intracellular TFV-DP and FTC-DP on both occasions. In addition to classic demographic and biologic covariates, three genetic polymorphisms were studied: MRP2 (rs717620), MRP4 (rs1751034), and MDR1 (rs1045642).
Results: A six compartments joint model was selected to describe the PK of the four compounds with common absorption mean transit time (MTT) and scale factor capturing correlations between apparent clearances and volumes. Plasma TFV and FTC diffuse each in two compartments and enter linearly into cell compartments to become TFV-DP and FTC-TP.
The final model fitted the data satisfactorily and contained an effect of age, MRP2 and MDR1 on MTT, creatinine clearance on both compounds clearances (CLTFV/F and CLFTC/F) and MRP2 on CLTFV.
TFDV and FTC t1/2 estimates were within the range of published values [1] but TFV-DP and FTC-TP estimates were twice as long. Consequently predicted average concentration for TFV-DP and FTC-TP at W4 were Cav,TFV-DP=137 fmol/106 cells and Cav,FTC-TP=8.4 pmol/106 cells, both consistent with literature values [1], but below their respective EC50 for competition with the HIV reverse transcriptase natural substrates [1]. Cav,TFV-DP was however above the EC50 for preventing cell infection [2].
Conclusions: Covariates on MTT had little impact, but patients with the lowest creatinine clearance and heterozygotes for MRP2 rs717620 had 86% and 39% higher Cav,TFV-DP and Cav,FTC-TP, respectively.
References:
[1] Duwal Sulav, Christof Schütte, and Max von Kleist. Pharmacokinetics and Pharmacodynamics of the Reverse Transcriptase Inhibitor Tenofovir and Prophylactic Efficacy against HIV-1 Infection. PLOS ONE (2012) 7 (7): e40382.
[2] Xinhui Chen, Sharon M. Seifert1, Jose R. Castillo-Mancilla, Lane R. Bushman, Jia-Hua Zheng, Jennifer J. Kiser, Samantha MaWhinney, Peter L. Anderson. Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates. PLOS ONE (2016) 11 (11):e0165505.
