Pharmacokinetic parameters of once-daily rilpivirine following administration of efavirenz in healthy subjects

Background: Rilpivirine and efavirenz share metabolic path-ways (CYP3A), potentially leading to drug-drug interactions. We report the pharmacokinetics, ex vivo antiviral activity and safety of rilpivirine, following efavirenz treatment. Methods: HIV-negative adults received in fixed sequence: treatment A (rilpivirine 25 mg once daily for 14 days, followed by a washout), treatment B (efavirenz 600 mg once daily for 14 days), immediately followed by treatment C (rilpivirine 25 mg once daily for 28 days). Rilpivirine pharmacokinetic profiles were determined on days 1 and 14 of treatment A and days 1, 14, 21 and 28 of treatment C. Ex vivo antiviral activity was measured in treatments A and C using an exploratory assay. Safety was evaluated throughout. Results: From days 1 to 21, higher mean rilpivirine exposure was observed with treatment A compared with treatment C. The area under the concentration-time curve (AUC(24 h)) least squares (LS) means ratio (90% CI) for treatment C versus treatment A was 0.54 (0.46, 0.64; Day 1), 0.82 (0.75, 0.89; Day 14) and 0.84 (0.74, 0.94; Day 21). By day 28 of treatment C, the main rilpivirine pharmacokinetic parameters were similar to day 14 of treatment A (AUC(24 h) LS means ratio [90% CI], 0.91 [0.82, 1.01]), except for the minimum plasma concentration. At each time point in treatment C, samples of > 80% of subjects demonstrated similar ex vivo antiviral activity compared with treatment A. All adverse events were grade 1 or 2. Conclusions: These results provide useful information supporting a clinical study evaluating HIV-1-positive subjects switching from efavirenz to rilpivirine.