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AIDS 2012: Long-acting HIV Integrase Inhibitor S/GSK1265744 May Allow Monthly Dosing


A nano-suspension formulation of the next-generation integrase inhibitor S/GSK1265744 demonstrated a half-life 21 to 50 days after a single injection, suggesting that once-monthly or even less frequent dosing may be possible, according to a poster presentation at the XIX International AIDS Conference (AIDS 2012) recently held in Washington, DC.

S/GSK1265744, being developed by Shionogi and ViiV Healthcare, previously showed potent antiviral activity as once-daily oral monotherapy, but a formulation that allows less-than-daily dosing would represent a revolution in antiretroviral treatment and potentially also HIV prevention.

William Spreen from GlaxoSmithKline and colleagues evaluated the pharmacokinetics, safety, and tolerability of a single dose of a long-acting parenteral (injected) formulation of S/GSK1265744 in healthy HIV negative adults.

In this Phase 1, double-blind, dose escalation study, 56 volunteers (31 men and 25 women) were randomly assigned to receive injections of a 200 mg/mL nano-suspension of S/GSK1265744 or else placebo injections.

Cohorts of 8 participants received intramuscular (IM) injections in the buttocks of 100 mg, 200 mg, 400 mg, or 800 mg (2 x 400 mg shots), or subcutaneous (SC) abdominal injections of 100 mg, 200 mg, or 400 mg (2 x 200 mg shots). In each cohort, 6 people received active drug and 2 got placebo.


  • S/GSK1265744 was detected in plasma up to 48 weeks after a single injection.
  • The nano-suspension drug exhibited absorption-limited kinetics, and giving split doses (2 injections at the same time) appeared increase the absorption rate.
  • S/GSK1265744 total concentration (area under the curve) appeared to increase proportionally to dose.
  • The average apparent half-life ranged from 21 to 50 days with the nano-suspension, compared to just 30 to 40 hours with oral dosing.
  • The 10-day concentration following an 800 mg IM dose was similar to the level that produced an HIV plasma viral load decrease of 2.5 log in prior studies of once-daily oral administration.
  • S/GSK1265744 LAP was generally well tolerated.
  • The most common adverse event was mild-to-moderate transient injection site reactions.
  • Reactions with erythema (redness) and nodules were more frequent with subcutaneous that with intramuscular injections.
  • There were no drug-related serious or grade 3-4 adverse events or laboratory abnormalities.

"S/GSK1265744 long-acting parenteral single dose IM or SC 100-800 mg was safe and generally well-tolerated," the investigators concluded. "Single SC or IM doses of the long-acting formulation yielded sustained S/GSK1265744 plasma concentrations previously shown to produce robust antiviral activity as oral monotherapy and suggest monthly to quarterly dosing intervals using clinically practical dose volumes."

"Modeling and simulation...suggest S/GSK1265744 long-acting parenteral200-400 mg monthly is an appropriate maintenance dose for HIV treatment," they noted. They indicated that S/GSK1265744 is also under evaluation for pre-exposure prophylaxis, or PrEP.

ViiV plans to start a Phase 2 clinical trial of theS/GSK1265744 nano-suspension in combination with a long-acting formulation of the NRTI rilpivirine (Edurant, formerly TMC278) as maintenance therapy, after participants achieve viral suppression using a traditional 3-drug regimen (S/GSK1265744 with either abacavir/lamivudine or tenofovir/emtricitabine) as induction therapy.



W Spreen, SL Ford, S Chen, et al. Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. XIX International AIDS Conference (AIDS 2012).  Washington, DC, July 22-27, 2012. Poster TUPE040.

Other Source 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. Last Updated on July 12, 2012.