期刊
CLINICAL DRUG INVESTIGATION
卷 39, 期 9, 页码 873-887出版社
ADIS INT LTD
DOI: 10.1007/s40261-019-00807-3
关键词
-
资金
- Genentech, Inc.
Background and Objective Current pain therapies often do not provide adequate pain relief and have dose-limiting adverse effects. Genetic evidence indicates that Na(V)1.7 sodium channels are required for pain transduction and therefore represent an important therapeutic target. GDC-0276 is a novel Na(V)1.7 inhibitor developed for the treatment of pain. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetics of orally administered GDC-0276 in healthy subjects. Methods This phase I, randomized, double-blind, placebo-controlled study assessed GDC-0276 as powder-in-capsule (PIC) or cyclodextrin solution (CD) single doses (SDs) of 2-270 mg (seven cohorts) and 45-540 mg (five cohorts), respectively. Multiple (MD) PIC doses were administered as total daily doses of 15-540 mg divided into two or three doses/day, up to 10 or 14 days. Safety was assessed by monitoring adverse events (AEs), vital signs, physical examinations, electrocardiograms, and laboratory tests for up to 15 days after the last day of dosing. GDC-0276 plasma pharmacokinetics were also determined. Results Three stages included 183 randomized subjects. GDC-0276 plasma exposure increased with dose level for all stages. Exposure was higher in the SD-CD cohorts compared with the equivalent SD-PIC dose levels. SDs were adequately tolerated up to 270 mg (SD-PIC) and 360 mg (SD-CD). Hypotension limited tolerability in the 540-mg SD-CD cohort. Multiple PIC doses were tolerated up to 270 mg twice daily, however liver transaminase elevations were frequently observed. No deaths or serious AEs occurred. Conclusion GDC-0276 exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for pain.
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