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Seven Short Studies Suggest Good Safety Profile of New Integrase Inhibitor
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49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), September 12-15, 2009, San Francisco
Mark Mascolini
Clinical side effects were rare and probability of a grade 2 or greater lab abnormality lay below 0.5% in an analysis of 7 brief clinical trials of S/GSK1349572, the integrase inhibitor being developed by Shinogi and GlaxoSmithKline [1]. This is an analysis including 166 people who took S/GSK1349572. Six of the trials involved healthy adults, while one involved 42 people with HIV infection, 35 of them taking S/GSK1349572.
GSK and Shinogi investigators scrutinized side effects and lab abnormalities recorded in the first 7 completed trials of S/GSK1349572, which proved potent in an early monotherapy study involving integrase inhibitor-naive people with HIV [2]. The safety analysis involved 18 people who took placebo and 166 people who took S/GSK1349572. Doses ranged from 2 to 100 mg in a single dose or multiple doses up to a maximum duration of 19 days.
Half of study participant taking S/GSK1349572 and half taking placebo had any side effect. Three of 183 people (1.6%) in these 7 trials dropped out because of adverse events, and 13 withdrew for other reasons. The most frequent problems that arose in 5 or more people taking the integrase inhibitor were headache (16%), diarrhea (7%), nausea (5%), dizziness (4%), and vomiting (4%).
There were no grade 4 adverse events. The four grade 3 events were joint pain judged not related to study drug in a healthy volunteer, migraine in an HIV-infected person, asymptomatic increased lipase in an HIV-infected person, and asymptomatic elevated triglycerides judged not related to study drug in an HIV-infected person. The investigators note that adverse events recorded in these studies are common in a confined population (conducted in closed hospital ward) and often caused by diet modification or caffeine restriction.
Statisticians figured the probability of a grade 2 or higher triglyceride, lipase, ALT, or AST abnormality at less than 0.5% among people taking S/GSK1349572. The most frequent grade 2 or higher abnormality was elevated glucose (in 3 people).
In people who had ECGs, 3000 machine-read ECGs disclosed an average -1.39 msec difference in QTcF between S/GSK1349572 and placebo. No study participant had a QTcF greater than 480 msec or a change from baseline greater than 60 msec. The investigators found no link between dose level or dosing duration and side effect rate, ECG change from baseline, or lab toxicities.
The researchers conclude that these studies identified no "significant safety signals after short-term dosing of S/SK1349572."
References
1. Lou Y, Min S, Chen S, et al. Meta-analysis of safety for short-term dosing of an HIV integrase inhibitor, S/GSK1349572, from seven clinical studies. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract H-931.
2. Lalezari J, Sloan L, Dejesus E, et al. Potent antiviral activity of S/GSK1349572, a next generation integrase inhibitor (INI), in INI-naive HIV-1-infected patients. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract TUAB105.
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