Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults
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 Injection | Subcutaneous Injection | ||||||
| S/GSK1265744 PK Parameter | 100mg | 200mg | 400mg | 800mg (400mg x2) | 100mg | 200mg | 400mg (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=4 | 1234 (418) | 2823 (1159) n=4 | 5860 (632) | 680 (208) n=5 | 1651 (31.3) n=4 | 2670 (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=4 | 50 (15) | 37 (25) n=4 | 21 (9.1) | 47 (20) n=5 | 45 (23) n=4 | 47 (27) |
[Mean Plasma S/GSK1265744 Conc-Time Profiles]
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