Presentation Abstract

Session: 143-HIV
Monday, Sep 14, 2009, 8:30 AM -11:00 AM
Presentation Title: H-1228 - 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
Location: Room 301
Presentation Number: H-1228
Pres. Time: Monday, Sep 14, 2009, 9:30 AM - 9:45 AM
Category: H
Keywords: HIV therapy; integrase inhibitor; clinical trial
Author(s): S. MIN1, E. DEJESUS 2, L. MCCURDY 2, G. RICHMOND 2, J. TORRES 2, S. FORD 1, S. CHEN 1, Y. LOU 1, M. BOMAR 1, T. CYR 1, T. FUJIWARA 3, M. ST. CLAIR 1, S. PISCITELLI 1;
1GSK, RTP, NC, 2ITZ111451 Investigators, RTP, NC, 3Shionogi & Co, LTD, Osaka, Japan.
Financial Disclosures:  S. Min,
GlaxoSmithKline Role(s): Employee, Received: Salary.
Abstract: Background: S/GSK1265744 (744) is an HIV integrase strand transfer inhibitor that demonstrates potent in vitro anti-HIV activity and a favorable preclinical profile. Methods: 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. Results: 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%) AUC0-24 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 IC90. Median elimination t1/2 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. Conclusions: 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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