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Background:  The drug 908 is a protease inhibitor (PI) with demonstrated antiviral efficacy, durability and tolerability in antiretroviral-naïve and PI-experienced subjects. 908, the phosphate ester pro-drug of amprenavir (APV), is rapidly converted to APV in vivo. 908 and lopinavir (LPV)/ritonavir (RTV) are both inhibitors and inducers of CYP3A4. All 3 PI are substrates for P-glycoprotein (P-gp) and have P-gp induction or inhibition properties. Previous data suggested that the combination of APV and LPV/RTV resulted in reduced plasma concentrations of APV and LPV. Therefore, 2 studies were conducted to assess potential interventions to overcome the pharmacokinetic interaction.

Methods:  Both studies were steady-state, open-label, randomized, balanced, 2x4 incomplete cross-over designs. Healthy adult subjects received study drugs for 14 days in each of 2 periods separated by a 28-day washout. In both studies, subjects received either 908 700 mg twice daily (BID) + RTV 100 mg BID (908+RTV) or LPV 400 mg/RTV 100 mg BID (LPV/RTV) as the control treatment. In study 1, subjects received the combination of 908 1400 mg BID + LPV 533 mg/RTV 133 mg BID (908+LPV/RTV). In study 2, subjects received the combination of 908 700 mg BID + RTV 100 mg BID and LPV 400 mg/RTV 100 mg BID (908+RTV+LPV/RTV). Serial PK sampling occurred on day 14 of each period. Treatment comparisons were assessed by ANOVA.

Results:  Of 36 subjects 23 completed study 1 and 20 completed study 2. In study 1, 10 of 13, and in study 2, 13 of 16 subjects who prematurely withdrew from the study withdrew due to adverse events, primarily due to gastrointestinal disturbances and rash. In study 1, 9 of 10 and in study 2, 10 of 13 subjects who withdrew due to adverse effects did so while receiving the combination.