Pharmacokinetic and pharmacokinetic/pharmacodynamic characterization of the dolutegravir/rilpivirine two‐drug regimen in SWORD‐1/‐2 phase 3 studies

Abstract

AimSWORD‐1 and SWORD‐2 phase 3 studies concluded that switching virologically suppressed participants with HIV‐1 from their current three‐ or four‐drug antiretroviral regimen (CAR) to the two‐drug regimen of once‐daily dolutegravir (DTG, 50 mg) and rilpivirine (RPV, 25 mg) was safe, well tolerated and noninferior for maintaining HIV‐1 suppression at week 48 and highly efficacious to week 148. A secondary objective was to characterize drug exposure and exposure‐efficacy/safety relationships.MethodsAdults with plasma HIV‐1 RNA <50 copies/mL were randomized to switch to once‐daily DTG + RPV on day 1 or to continue CAR for 52 weeks before switching. Trough plasma concentrations (C0) of DTG and RPV, the proportion of participants with HIV‐1 RNA <50 copies/mL and adverse events to week 100 were summarized and subjected to exposure‐response analyses in the overall population, in the subset of participants who switched from CAR containing enzyme‐inducing drugs and by age category (≥50 and <50 years). The relationship between C0avg (individual average C0 across visits) and efficacy/safety was investigated.ResultsAlthough week 2 DTG and RPV C0 were lower in participants switching from enzyme‐inducing antiretroviral drugs, C0 and C0avg stayed above in vitro antiviral protein binding‐adjusted IC90 and to week 100 with viral suppression >89%. DTG or RPV C0avg showed no relationship with virologic failures or safety. Participants ≥50 years had similar C0avg and safety response to younger participants.ConclusionNo clinically relevant relationship between DTG or RPV exposures and virologic or safety response was observed, confirming the DTG + RPV switch for participants as a safe and effective treatment.