Integrase inhibitors, a new class of antiretroviral agents that prevent HIV from inserting its genetic material into host cells, received considerable attention at the 14th Conference on Retroviruses and Opportunistic Infections held last week in Los Angeles, including presentations on Merck's raltegravir (MK-0518) and Gilead Science's elvitegravir (GS-9137).

GlaxoSmithKline (GSK) is also working on an integrase inhibitor candidate known as GSK364735. Researchers from GSK and Shinogi USA presented data from a randomized, double-blind, placebo-controlled, Phase I study comparing the safety, tolerability, and pharmacokinetics of single and multiple doses of GSK364735 in 79 healthy HIV negative volunteers.

In the first part of the study, subjects received single doses of GSK364735, ranging from 50 to 400 mg on an empty stomach; 200 mg and 400 mg doses with food; a 50 mg dose boosted with 100 mg ritonavir; and a 200 mg dose co-administered with Maalox. In the second part, 5 groups received repeated doses of 100 to 600 mg GSK364735 once-daily with food for 7 days.

Results

• Pharmacokinetic assessments showed that GSK364735 concentrations increased with food.

• Ritonavir did not significantly alter the pharmacokinetics of GSK364735.

• GSK364735 did not inhibit or induce cytochrome P450 enzymes, except for a weak inhibition of CYP1A2.

• Overall, GSK364735 was well-tolerated in healthy patients.

• Drug-related adverse events were mostly mild, and none were serious or led to treatment discontinuation.

• No Grade 2 or higher laboratory abnormalities or significant changes in vital signs or electrocardiograms were reported.

GSK364735 is now undergoing Phase II trials in HIV positive patients.

GlaxoSmithKline, Research Triangle Park, NC; Shionogi USA, Inc, Florham Park, NJ.

Link to study abstract.

03/06/07

Reference
S Reddy, S Min, J Borland, and others. A Double-blind, Parallel, Randomized, Placebo-controlled, Single and Repeat Dose-escalation Study to Investigate the Safety, Tolerability, and Pharmacokinetics of the HIV Integrase Inhibitor GSK364735 in Healthy Subjects (GRZ105655). 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles. February 25-28, 2007. Abstract 562 (poster).