Combined population pharmacokinetic model of tenofovir and emtricitabine and their active intracellular metabolites in HIV Patients from the ANRS 134-COPHAR 3 trial

Tenofovir (TFV) and emtricitabine (FTC), which are part of the recommended highly active antiretroviral therapy for naïve HIV patients, show a large inter-individual pharmacokinetic (PK) variability so far unexplained.

We model the concentrations of plasma TFV and FTC and their intracellular metabolites (TFV-DP and FTC-TP) collected after 4 and 24 weeks of treatment in 34 treatment naïve patients from the ANRS 134-COPHAR 3 trial receiving atazanavir (300 mg), ritonavir (100 mg) and a fixed-dose combination of co-formulated nucleoside analogs TFV disoproxil fumarate (300 mg) and FTC (200 mg). A six compartment model was selected to describe the PK of the four compounds. Both TFV and FTC clearances increased with creatinine clearance and TFV clearance was decreased by 18% in patients ABCC2 CT.

The model was used to compare average intracellular  at steady state assuming total adherence following 7-days-a week (such as in the ANRS 134-COPHAR 3 trial) and 4-days-a-week regimen (such as proposed in the ANRS 162-4D trial). Considering the 50th predicted percentile at steady state, the nadir over a two-week window for FTC-TP during the 4-days-a-week treatment is 3.3 pmol/106 cells compared to 7.6 pmol/106 cells during the 7-days-a week treatment (ratio of 2.3) while for TFV-DP it is 74.9 fmol/106 cells compared to 140.3 fmol/106 cells (ratio of 1.9).

Our model provide estimates of FTC-TP and TFV-DP average concentrations in HIV patients in viral success, but also simulated values for a treatment alternative improving patient quality of life, which achieved on trial a 96% viral success.