Lack of pharmacokinetic interaction between rilpivirine and integrase inhibitors dolutegravir and GSK1265744

Abstract

Dolutegravir (DTG) and GSK1265744 are HIV integrase inhibitors (INIs) in clinical development. The oral formulation of rilpivirine (RPV), a nonnucleoside reverse transcriptase inhibitor (NNRTI), has been approved for treatment-naive HIV infection. Long-acting depot injections of GSK1265744 and RPV are also being developed. This study evaluated the potential for drug interactions between RPV and these INIs. This phase 1, open-label, two-cohort, three-period, single-sequence crossover study evaluated oral coadministration of RPV with DTG or GSK1265744. Healthy subjects received DTG (50 mg every 24 h for 5 days) or GSK1265744 (30 mg every 24 h for 12 days) in period 1 followed by a washout, RPV (25 mg every 24 h for 11 or 12 days) in period 2, immediately followed by RPV (25 mg every 24 h) plus DTG (50 mg every 24 h) for 5 days or GSK1265744 (30 mg every 24 h) for 12 days in period 3. Steady-state pharmacokinetic (PK) parameters were estimated using noncompartmental analysis of data collected on the last day of each period. The combinations of RPV and DTG (n = 16) and of RPV and GSK1265744 (n = 11) were well tolerated; no grade 3 or 4 adverse events (AEs) or AE-related discontinuations were observed. The 90% confidence intervals for the area under the curve from time zero until the end of the dosage interval [AUC0-τ] and maximum concentration of drug in serum (Cmax) geometric mean ratios were within 0.8 to 1.25. Following administration of DTG + RPV, DTG and RPV Cτ increased by 22% and 21%, respectively. Following administration of GSK1265744 + RPV, RPV Cτ decreased 8%. DTG and GSK1265744 can be administered with RPV without dosage adjustment for either agent. These results support coadministration of RPV with DTG or GSK1265744 as either oral or long-acting depot injection regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01467531.).

Fig 1

Mean (SD) steady-state DTG concentration-time profiles following administration of DTG with and without RPV.

Fig 2

Mean (SD) steady-state GSK1265744 concentration-time profiles following administration of GSK1265744 with and without RPV.

Fig 3

Mean (SD) steady-state plasma RPV concentration-time profiles following administration of RPV with and without DTG or GSK1265744.