Monday, Sep 14, 2009, 8:30 AM -11:00 AM
Pharmacokinetics (PK) and Safety in Healthy and HIV-Infected Subjects and Short-Term Antiviral Efficacy of S/GSK1265744, a Next Generation Once Daily HIV Integrase Inhibitor
Monday, Sep 14, 2009, 9:30 AM - 9:45 AM
HIV therapy; integrase inhibitor; clinical trial
, E. DEJESUS
, L. MCCURDY
, G. RICHMOND
, J. TORRES
, S. FORD
, S. CHEN
, Y. LOU
, M. BOMAR
, T. CYR
, T. FUJIWARA
, M. ST. CLAIR
, S. PISCITELLI
GSK, RTP, NC,
ITZ111451 Investigators, RTP, NC,
Shionogi & Co, LTD, Osaka, Japan.
S/GSK1265744 (744) is an HIV integrase strand transfer inhibitor that demonstrates potent in vitro anti-HIV activity and a favorable preclinical profile.
A double-blind, randomized, placebo-controlled single (Part A) and multiple (Part B) oral dose escalation was conducted in 48 healthy subjects (38 A/ 10 P), and a double blind, randomized, placebo-controlled multiple oral dose study (Part C) was conducted in 11 (8 A/ 3 P) HIV-infected subjects. During Part A, 2 cohorts of 9 subjects received alternating suspension doses of 5, 10, 25 and 50mg. During Part B, 3 cohorts of 10 subjects received suspension doses of 5, 10, or 25mg once daily for 14 days. During Part C, subjects received 30mg (6 - 5 mg tablets) once daily for 10 days, followed by 14 days of 3-drug antiretroviral therapy. Lab tests, vital signs, ECG, and PK sampling were performed at regular intervals.
Most adverse events were mild; headache was most common. No lab or ECG trends were noted. PK was dose-proportional over the dosage range studied in healthy subjects. Steady-state geometric mean (CV%) AUC
and Cmax ranged from 32.5 (16%) ug*h/mL and 2.1 (19%) ug/mL at 5 mg QD to 160 (20%) ug*h/mL and 9.5 (19%) ug/mL at 25mg, respectively, and steady-state C24 at 25mg solution QD was 5.4 ug/mL, >30-fold above the protein-adjusted IC
. Median elimination t
was 30-40 hrs. HIV-infected subjects receiving 744 had a mean decrease from baseline on Day 11 in plasma HIV-1 RNA of 2.34 log10 copies/mL.
S/GSK1265744 was well tolerated in healthy and HIV-infected subjects. The PK profile indicated that once daily tablet doses of ≤30 mg would achieve target therapeutic concentrations. Potent short-term antiviral efficacy was shown with 30mg once daily dosing. Additional evaluation in HIV-infected patients is planned.
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