Category: A1
S. L. FORD, M. B. WIRE, Y. LOU, K. L. BAKER, D. S. STEIN;
GlaxoSmithKline, Research Triangle Park, NC.
Presentation Number: A-1606
Keywords: GW433908, protease inhibitor, drug interactions
Background: 908 is an investigational HIV protease inhibitor (PI) with demonstrated antiviral efficacy, durability and tolerability in ART-naïve and PI experienced subjects. 908, the phosphate ester prodrug of amprenavir (APV), undergoes conversion to APV during absorption with negligible 908 systemic exposure. Chemical properties of 908 suggested an interaction with antacids by two potential mechanisms, either by phosphate chelation by metal cations (Al3+/Mg2+) or decreased 908 solubility at increased pH. Methods: 26 healthy subjects completed this single-dose, open-label, randomized, three-way, balanced, crossover study. Treatments included 908 alone, 908 with MAALOX TC® (MLX) 30mL, and 908 1-h after Ranitidine (ZANTAC®, ZAN) 300mg (908 dose = 1400mg for all). Serial plasma samples were collected over 24-h and assayed by LC/MS/MS. Non-compartmental PK analysis of plasma APV concentration-time data was performed. Geometric least square mean (GLSM) ratios with 90% confidence intervals (CI) for MLX/908 and ZAN/908 treatment comparisons were determined for plasma AUClast, Cmax, and C12. Results: Co-administration of 908 with MLX decreased plasma APV AUClast by 18% [GLSM ratio (CI) = 0.82 (0.74-0.91)], decreased Cmax by 35% [0.65 (0.57-0.76)], and increased C12 by 14% [1.14 (0.93-1.39)]. Co-administration of 908 after ZAN decreased plasma APV AUClast by 30% [0.70 (0.63-0.78)], decreased Cmax by 51% [0.49 (0.42-0.57)], but did not change plasma C12 [0.99 (0.81-1.21)]. Conclusions: Following single dose administration, both MLX and ZAN moderately reduced APV AUClast and Cmax when co-administered with 908, but neither reduced APV C12. Increased gastric pH is the likely interaction mechanism. Based on the magnitude of the interactions seen, these results are unlikely to be of clinical significance when co-dosing 908 with either MLX or ZAN.
Commercial Relationship: S.L. Ford, GlaxoSmithKline F.
PresentationPreference: Poster NoOffLabel: True