Assessment of the steady-state drug-drug interactions between dolutegravir and ritonavir-boosted darunavir in adolescents

Objectives: DTG is primarily metabolized by the UDP-glycosyltransferase (UGT) 1A1, and to a lesser extent by the cytochrome P450 (CYP) 3A4. Co-administration of DRV/r has been reported to decrease DTG plasma concentrations. Our aim was to distinguish the extent of the drug – drug interactions between DRV/r and DTG, and to evaluate the consequences of this interaction, in adolescents at steady state. Design: SMILE (PENTA 17-ANRS152) was a phase II/III trial assessing the safety and efficacy of once-daily dual therapy, using dolutegravir (DTG) combined with ritonavir-boosted darunavir (DRV/r), in virologically suppressed adolescents aged 12 years and older. Methods: A joint population pharmacokinetic model for DTG and DRV/r was developed with prior individual drug models (involving unbound and total concentrations) using SMILE data. Results: Unbound DRV exposure, integrated as a power function on unbound DTG clearance best described DRV/r inhibition of DTG elimination. Nevertheless, no interaction was identified between DRV/r and total DTG clearance. Moreover, the influence of unbound DRV exposures to predict unbound DTG concentrations was relatively small.