Background:  JTK-303/GS 9137 is a novel HIV integrase inhibitor with potent in vitro anti-HIV activity and is being developed for treatment of HIV infection. We wanted to assess its safety, tolerability, and pharmacokinetics.

Methods:  A single blind, randomized, placebo-controlled, single oral dose-escalation study was conducted in 32 healthy male Japanese volunteers. Doses of 100, 200, 400, or 800 mg were given to 8 fasting subjects (6 active and 2 placebo) per cohort. In addition, the subjects in the 400-mg cohort also received an additional 400-mg dose with breakfast after a washout period. For the evaluation of pharmacokinetics, blood samples for determination of JTK-303 plasma concentrations were collected over 24 hours post-dose. Laboratory safety tests, vital signs, and electrocardiography (ECG) were performed throughout the study.

Results:  JTK-303 was safe and well tolerated with no serious adverse events and no grade 3 or 4 adverse events in any cohort. All adverse events were mild. One subject experienced mild anorexia and another experienced mild laboratory abnormalities. No clinically significant ECG changes were noted. In the ascending dose portion, plasma concentrations of JTK-303 attained C_max at 0.5 to 4 hours post-dose. C_max and area under the curve (AUC) of JTK-303 increased with dose escalation from 100 to 800 mg. Food significantly increased the C_max and AUC of JTK-303, approximately 3-fold relative to administration in the fasted state. Plasma concentrations of JTK-303 at 12 to 24 hours exceeded protein binding-adjusted in vitro EC₉₀ concentrations.

Conclusions:  JTK-303 is orally bioavailable, safe, and well tolerated following single doses. These data support further investigations of JTK-303, including in HIV-infected individuals.