Population Pharmacokinetic Analysis of Dolutegravir in Treatment‐Experienced Adults Living with HIV‐1

Abstract

The World Health Organization has recommended the use of dolutegravir (DTG) for both first and second‐line antiretroviral treatment in both adults and children down to 4 weeks of age. We developed a population pharmacokinetic(PopPK) model following oral administration of DTG 50 mg QD and 50 mg BID in HIV‐infected treatment‐experienced adults (607) based on pooled data from four phase 2/3 trials. DTG population pharmacokinetics are described by a one‐compartment model with first‐order absorption, absorption lag‐time, and first‐order elimination. The PopPK parameter estimates were apparent oral clearance (CL/F) = 1.00 L/h, apparent volume of distribution (V/F) = 18.9 L, absorption rate constant (Ka) = 1.99 per hour, and absorption lag time = 0.333 h, respectively. The final model included inter‐individual and inter‐occasion variability on apparent clearance (CL/F). Weight, smoking status, use of metabolic inducers as part of background antiretroviral therapy (ART) classified by their level of induction, use of atazanavir or atazanavir‐ritonavir as part of background ART, and albumin level were predictors of CL/F; weight and albumin level were predictors of V/F; and sex and concomitant use of metal cation‐containing vitamin/mineral supplements were predictors of relative bioavailability (F). The current model‐based analysis suggests that the DTG dose adjustment is not required based on the demographics, laboratory values, smoking status, concomitant use of mild metabolic inducers or inhibitors in the background therapy, or use of metal cation‐containing vitamin/mineral supplements because these covariate effects are not predicted to have a clinically relevant impact on safety and efficacy.