XIX International AIDS Conference


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TUPE040 - Poster Exhibition

Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults

W. Spreen1, S.L. Ford1, S. Chen1, E. Gould1, D. Wilfret1, D. Subich2, T. Taishi3, Z. Hong1

1GlaxoSmithKline, Infectious Diseases R&D, Research Triangle Park, United States, 2Covance Clinical Research Unit, Daytona Beach, United States, 3Shionogi Pharmaceuticals, Osaka, Japan

Background: S/GSK1265744, an HIV integrase inhibitor with proven antiviral activity following oral monotherapy, is under development as a long-acting parenteral (LAP) depot formulation. Antiretrovirals dosed monthly to quarterly may provide clinical utility for HIV treatment and prevention. This study evaluated pharmacokinetics (PK), safety, and tolerability of single S/GSK1265744 LAP doses in healthy adults.
Methods: This was a Phase I, randomized, double-blind, placebo-controlled, dose escalation study. S/GSK1265744 200mg/mL nanosuspension was administered by intramuscular (IM) gluteal injection [100mg, 200mg, 400mg, 800mg (400mg x2)] or subcutaneous (SC) abdominal injection [100mg, 200mg, 400mg (200mg x2)] to cohorts of eight (6 active/2 placebo) subjects. Safety and PK were assessed prior to dose escalation and continued until plasma S/GSK1265744 was < 0.1ug/mL by LC/MS/MS; PK parameters were determined by noncompartmental methods.
Results: Twenty-five females and 31 males were dosed; S/GSK1265744 LAP was generally well tolerated with mild-moderate, self-limited injection site reactions (ISR) reported as the most common adverse event (AE); ISR erythema and nodules were more frequent following SC dosing. Systemic safety was good with no drug-related serious AEs or Grade 3-4 AEs. S/GSK1265744 was detected in plasma up to 48 weeks and exhibited absorption-limited kinetics; mean apparent terminal phase t1/2 ranged 21-50 days vs. 40h following oral dosing. S/GSK1265744 AUC(0-∞) appeared to increase proportionally to dose. Split dosing increased the apparent absorption rate. Mean S/GSK1265744 Cday10 following 800mg IM was similar to geometric mean Ct,ss of 3.28ug/mL associated with -2.5log10 mean change in plasma HIV RNA following 10days of 30mg PO QD monotherapy.
Conclusions: S/GSK1265744 LAP single dose IM or SC 100-800mg was safe and generally well-tolerated. Achievement of sustained plasma concentrations previously shown to produce >2.5log10 mean reduction of HIV RNA as monotherapy suggest S/GSK1265744 LAP may exhibit prolonged antiviral activity at clinically practical doses and supports continued development.

 Regimen (n=6/dose group unless otherwise noted)
 Intramuscular InjectionSubcutaneous Injection
S/GSK1265744 PK Parameter100mg200mg400mg800mg (400mg x2)100mg200mg400mg (200mg x2)
AUC(0-day28) (ug*h/mL)141 (92.4)140 (36.3)299 (126)1752 (862)96.2 (40.2)284 (124)410 (216)
AUC(0-∞) (ug*h/mL)881 (104) n=41234 (418)2823 (1159) n=45860 (632)680 (208) n=51651 (31.3) n=42670 (655)
Cmax (ug/mL)0.304 (0.158)0.347 (0.095)0.851 (0.502)4.01 (2.49)0.253 (0.145)0.626 (0.327)1.15 (0.990)
tmax (days) [median (range)]9.0 (4-83)45.5 (27-167)83 (20-195)7.5 (5-139)16.5 (4-55)6.0 (3-27)27 (3-83)
Cday10 (ug/mL)0.256 (0.177)0.214 (0.67)0.503 (0.217)3.46 (1.86)0.128 (0.023)0.445 (0.178)0.485 (0.185)
Cday28 (ug/mL)0.200 (0.134)0.258 (0.087)0.561 (0.350)2.39 (1.05)0.197 (0.126)0.534 (0.371)1.07 (1.03)
Apparent t1/2 (days)47 (30) n=450 (15)37 (25) n=421 (9.1)47 (20) n=545 (23) n=447 (27)
[Mean (SD) Plasma S/GSK1265744 PK Parameters]

Mean Plasma S/GSK1265744 Conc-Time Profiles
[Mean Plasma S/GSK1265744 Conc-Time Profiles]

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