Pharmacokinetics, Safety, and Monotherapy Antiviral Activity of GSK1265744, an HIV Integrase Strand Transfer Inhibitor

Abstract

Background: GSK1265744 is an HIV integrase strand transfer inhibitor selected for clinical development. Objective: This first-time-in-human and phase IIa investigation assessed GSK1265744 antiviral activity, pharmacokinetics, safety, and tolerability in healthy and HIV-1–infected subjects. Methods: This double-blind, placebo-controlled study consisted of a dose escalation of single (part A) and multiple (part B) oral doses in 48 healthy subjects and an oral dose (part C) in 11 HIV-1–infected subjects. In part A, 2 cohorts of 9 subjects received either 5 and 25 mg or 10 and 50 mg. In part B, 3 cohorts of 10 subjects received 5, 10, or 25 mg once daily for 14 days. In part C and the phase IIa study, subjects received 5 or 30 mg once daily for 10 days. Results: Dose-proportional increases in drug exposure were observed in healthy and HIV-1–infected subjects. In healthy subjects, pharmacokinetic variability was low following single or repeat dosing (coefficient of variation, 13%-34% and 15%-23%, respectively). Mean plasma half-life was 31.5 hours. GSK1265744 monotherapy significantly reduced plasma HIV-1 RNA from baseline to day 11 in HIV-1–infected subjects receiving 5 or 30 mg versus placebo (P < .001); mean decrease was 2.2 to 2.3 log10 copies/mL, respectively. Study drug was generally well tolerated with no clinically relevant trends in laboratory values, vital signs, or electrocardiograms. Conclusions: GSK1265744 was well tolerated in healthy and HIV-1–infected subjects. Results demonstrate once-daily doses of 5 or 30 mg exceeded minimum target therapeutic concentrations and produced a significant reduction in plasma HIV-1 RNA viral load.