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Pharmacokinetics (PK) and safety in healthy subjects of S/GSK1349572, a next generation, once-daily HIV integrase inhibitor (INI)
S. Min1, I. Song2, J. Borland3, S. Chen4, Y. Lou4, T. Fujiwara5, S. Piscitelli6
1GlaxoSmithKline, ID MDC, Research Triangle Park, United States, 2GlaxoSmithKline, CPKMS, Research Triangle Park, United States, 3GlaxoSmithKline, CSSO, Research Triangle Park, United States, 4GlaxoSmithKline, BDS, Research Triangle Park, United States, 5Shionogi & Co., Ltd., Osaka, Japan, 6GlaxoSmithKline, Infectious Diseases Medicine Development Center, Research Triangle Park, United States
Background: S/GSK1349572 is an HIV integrase strand transfer inhibitor that demonstrates potent in vitro anti-HIV activity and a favorable preclinical profile.
Methods: Randomized, double-blind, placebo-controlled first in human single-dose (SD) and multiple-dose (MD), dose escalation studies were conducted. In the SD study, 2 cohorts of 10 subjects (8 active, 2 placebo) received suspension doses of 2, 5, 10, 25, 50 and 100 mg in an alternating panel design. In the MD study, 3 cohorts of 10-12 subjects (8 or 10 active, 2 placebo) received suspension doses of 10, 25 and 50mg once daily for 10 days, and a CYP3A substrate, midazolam, was given on Day -1 alone and on Day 10 with the 25 mg dose. An additional 12 subjects received 20mg suspension and two 10mg tablets with and without a 30% fat meal in a crossover design. Laboratory testing, vital signs, ECGs and PK sampling were performed at regular intervals.
Results: Most adverse events (AE) were mild; headache was the most common AE. No laboratory or ECG trends were noted. PK was dose proportional and time-invariant over the dosage range studied. Median elimination half-life was 15 hours. Steady state geometric mean (CV%) AUC(0-24) and Cmax ranged from 16.7 (15) ug*h/mL and 1.5 (24) ug/mL at 10 mg once daily to 76.8 (19) ug*h/mL and 6.2 (15) ug/mL at 50mg once daily, respectively. The geometric mean steady-state C24 at 50mg was 1.5 ug/mL, ~23-fold higher than the in vitro protein-adjusted IC90. GSK1349572 had no impact on midazolam PK. The tablet demonstrated relative bioavailability of 70% compared to suspension. Food had no impact on tablet exposure.
Conclusions: S/GSK1349572 was well tolerated in healthy subjects. The PK profile indicates once daily low doses of S/GSK1349572 will achieve target therapeutic concentrations. S/GSK1349572 does not affect CYP3A. S/GSK1349572 is being evaluated in HIV-infected patients.
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