Discussion
-- S/GSK1265744 long acting parenteral administration prolonged plasma levels (apparent t1/2of 2150days; Figure 4) compared with oral administration (oral t1/2of 30-40 hours)
-- AUC(0-∞)appeared to increase in a dose-proportional manner; Cmax increased greater than proportional to dose following 800 mg IM, suggesting the rate of absorption was higher for this dose (Table 2)
-- 800 mg IM achieved a mean S/GSK1265744 Cday 1021-fold above PA-IC90; this exposure is comparable to exposure observed with 30 mg oral, once-daily dosing, which produced a -2.5 log10decrease in HIV RNA following 10 days of monotherapy in HIV-infected subjects. Mean Cday28following 800 mg IM was 14-fold above PAIC90, making this a viable loading dose for S/GSK1265744 LAP
-- Modeling and simulation (not shown) suggest S/GSK1265744 LAP 200-400 mg monthly is an appropriate maintenance dose for HIV treatment
Conclusions
S/GSK1265744 LAP single dose IM or SC 100-800 mg was safe and generally well tolerated in healthy adult subjects. Both IM and SC routes of administration will be evaluated in repeat-dose clinical trials
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
Study results support continued development; S/GSK1265744 is under evaluation for both HIV prevention as pre-exposure prophylaxis as well as HIV therapy with a partner antiretroviral agent, rilpivirine (TMC278-LA)
Abstract
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 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
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