Effects of Etravirine Alone and with Ritonavir-Boosted Protease Inhibitors on the Pharmacokinetics of Dolutegravir ▿

Dolutegravir (DTG) is an unboosted, once-daily integrase inhibitor currently in phase 3 trials. Two studies evaluated the effects of etravirine (ETR) alone and in combination with ritonavir (RTV)-boosted protease inhibitors (PIs) on DTG pharmacokinetics (PK) in healthy subjects. DTG 50 mg every 24 h (q24h) was administered alone for 5 days in period 1, followed by combination with ETR at 200 mg q12h for 14 days in period 2 (study 1) or with ETR/lopinavir (LPV)/RTV at 200/400/100 mg q12h or ETR/darunavir (DRV)/RTV at 200/600/100 mg q12h for 14 days in period 2 (study 2). PK samples were collected on day 5 in period 1 and day 14 in period 2. All of the treatments were well tolerated. ETR significantly decreased exposures of DTG, with geometric mean ratios of 0.294 (90% confidence intervals, 0.257 to 0.337) for the area under the curve from time zero until the end of the dosage interval (AUC 0-τ ), 0.484 (0.433 to 0.542) for the observed maximum plasma concentration ( C max ), and 0.121 (0.093 to 0.157) for the plasma concentration at the end of the dosage interval ( C τ ). ETR combined with an RTV-boosted PI affected the exposure of DTG to a lesser degree: ETR/LPV/RTV treatment had no effect on the DTG plasma AUC 0-τ and C max , whereas the C τ increased by 28%. ETR/DRV/RTV modestly decreased the plasma DTG AUC 0-τ , C max , and C τ by 25, 12, and 37%, respectively. Such effects of ETR/LPV/RTV and ETR/DRV/RTV are not considered clinically relevant. The combination of DTG and ETR alone should be avoided; however, DTG may be coadministered with ETR without a dosage adjustment if LPV/RTV or DRV/RTV is concurrently administered.