icon-    folder.gif   Conference Reports for NATAP  
  XIX International AIDS Conference
July 22-27, 2012
Washington, DC
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Pharmacokinetics, Safety and Tolerability of the HIV Integrase Inhibitor S/GSK1265744 Long Acting Parenteral Nanosuspension Following Single Dose Administration to Healthy Adults
  Reported by Jules Levin
19th International AIDS Conference; July 22-27, 2012; Washington, DC
W Spreen,1SL Ford,1S Chen,1E Gould,1D Wilfret,1D Subich,2T Taishi,3Z Hong1 1GlaxoSmithKline, Infectious Diseases R&D, Research Triangle Park, NC, United States; 2Covance Clinical Research Unit, Daytona Beach, FL, United States; 3Shionogi & Co, Ltd, Osaka, Japan
Not yet recruiting Dose Ranging Study of GSK1265744 Plus Nucleoside Reverse Transcriptase Inhibitors for Induction of Human Immunodeficiency Virus-1 (HIV-1) Virologic Suppression Followed by Virologic Suppression Maintenance by GSK1265744 Plus Rilpivirine


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 200 mg/mL nanosuspension was administered by intramuscular (IM) gluteal injection (100 mg, 200 mg, 400 mg, 800 mg [400 mg x2]) or subcutaneous (SC) abdominal injection (100 mg, 200 mg, 400 mg [200 mg 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 <0.1 μg/mL by LC/MS/MS; PK parameters were determined by noncompartmental methods.
Results: 25 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 t1/2ranged 2150days vs. 40 h following oral dosing. S/GSK1265744 AUC(0-∞) appeared to increase proportionally to dose. Split dosing increased the apparent absorption rate. Mean S/GSK1265744 Cday 10 following 800 mg IM was similar to geometric mean Cτ,ss of 3.28μg/mL associated with -2.5 log10mean change in plasma HIV RNA following 10 days of 30 mg PO QD monotherapy.
Conclusions: S/GSK1265744 LAP single dose IM or SC 100-800 mg was safe and generally well tolerated. Achievement of sustained plasma concentrations previously shown to produce >2.5 log10mean reduction of HIV RNA as monotherapy suggests S/GSK1265744 LAP may exhibit prolonged antiviral activity at clinically practical doses and supports continued development.
S/GSK1265744 is an integrase strand transfer inhibitor in development as both an oral formulation and LAP injection. The compound has attributes that enable formulation and delivery as a nanosuspension for injection:
-- High potency: deliver monthly or longer dose in clinically practical volume -- Low aqueous solubility and correct particle size to control release kinetics -- Low metabolic clearance: reduced drug input requirement -- Formulation prerequisites: withstand nanomilling forces, stability in formulation with excipients and stabilizers, a sterile product
Prior clinical studies have demonstrated S/GSK1265744 oral monotherapy produces a vigorous antiviral effect in HIV-infected subjects at 5 or 30 mg once daily for 10 days (Figure 1). In vitro resistance studies suggest a favorable profile. The current study was undertaken to evaluate the safety and PK of single IM or SC doses of S/GSK1265744 LAP formulation in healthy adult subjects