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Meta-analysis of Safety Data From 8 Clinical Studies With GSK1265744, an HIV Integrase Inhibitor, Dosed Orally or as Injection of Long-Acting Parenteral Nanosuspension (LAP)
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Reported by Jules Levin
ICAAC Sept 10-13 2013 Denver, Colorado
Y Lou, E Gould, S Chen, D Wilfret, W Spreen, S Piscitelli, D Margolis
GlaxoSmithKline, Research Triangle Park, NC, USA
ABSTRACT
Background: GSK1265744 (GSK744) is an investigational integrase inhibitor with robust antiviral activity dosed in clinical trials as a once-daily oral tablet (t· ~40 hours) or long-acting parenteral (LAP) injection at intramuscular (IM) or subcutaneous (SC) sites (t· ~30-40 days). Safety was evaluated from phase I and IIa studies across various dosing routes and treatment durations.
Methods: Safety analysis included 6 short-term healthy or HIV-infected subject oral dosing studies and 2 healthy subject LAP studies dosed as single or repeat monthly (x4) or quarterly (x2) injections with relevant clinical exposures exceeding 6 months. Oral GSK744 5-50 mg was administered up to 14 days (n=187) and LAP as 100-800 mg IM or 100-400 mg SC injections in single (n=58) or repeat doses (n=40). Adverse events (AEs), laboratory parameters and ECGs were pooled across studies and summarized.
Results: GSK744 was administered to 245 subjects across all studies. There were no drug-related SAEs. The most frequent (>5%) non-injection site reaction (ISR)-related AEs were headache (22%) and nausea (5%). Two Grade 3 AEs (creatine kinase [CK], bilirubin) and 2 Grade 4 AEs (CK, osteomyelitis) were reported as unrelated to GSK744. Treatment-emergent ≥ Grade 2 laboratory abnormalities were infrequent: total cholesterol (5%), lipase (4%), bilirubin (2%), glucose (2%) and CK (2%). 2540 post-dose ECGs were evaluated; the difference in mean change in QTcF from baseline between GSK744 and placebo groups was -2.9 msec. No relationship was observed between dose and non-ISR AE rate, ECG change from baseline and laboratory test abnormalities. ISR AEs related to GSK744 LAP injection were largely mild (93%) with no Grade 3 ISR AEs. The most frequent ISR AEs for IM and SC dosing were pain (71% and 24%), erythema (9% and 23%) and nodules (7% and 23%). Median IM ISR AE durations were ~5 days for both pain and erythema and ~22 days for nodules. There were no ISR AE-related withdrawals.
Conclusion: GSK744 as single and repeat oral doses up to 50 mg and SC/IM LAP injections up to 800 mg were well tolerated. All ISR AEs were self-limited and predominantly Grade 1. Safety analyses support continued development of both oral and parenteral GSK744 formulations.
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