WEAB0103 - Oral Abstract
First study of repeat dose co-administration of GSK1265744 and TMC278 long-acting parenteral nanosuspensions: pharmacokinetics, safety and tolerability in healthy adults
Presented by William Spreen (United States).
W. Spreen1, P. Williams2, D. Margolis1, S. Ford1, H. Crauwels2, Y. Lou1, E. Gould1, M. Stevens2, S. Piscitelli1
1GlaxoSmithKline, Infectious Diseases Research & Development, Research Triangle Park, United States, 2Janssen Infectious Diseases BVBA, Beerse, Belgium
Background: Long acting parenteral (LAP) antiretrovirals may offer more convenient treatment options for certain HIV-infected patients. PK, safety, and tolerability of the integrase inhibitor GSK1265744 (GSK744) and the NNRTI TMC278 LA were assessed after repeat dose administration in healthy subjects.
Methods: Subjects received a 14 day lead-in of oral GSK744 30mg/day to assess safety and tolerability before LAP administration. Subjects were randomized into 4 cohorts: GSK744 800mg IM followed by three monthly doses of (1) 200mg SC; (2) 200mg IM; (3) 400mg IM; or (4) after 3 months a single further injection of 800mg IM. Cohorts 2 and 3 also received IM doses of TMC278 LA at months 3 (1200mg) and 4 (900 or 600mg, respectively). PK and safety were assessed throughout the trial.
Results: 47 subjects enrolled; 40 received ≥1 LAP injection with 38 completing all planned injections. Seven subjects discontinued GSK744 oral (non-drug related n=6, dizziness n=1). GSK744 LAP and TMC278 LA therapy was generally well tolerated with grade 1 injection site reactions most-commonly reported. Three subjects discontinued during injection phase (consent withdrawn n=2, self-limited rash n=1). There was one subject with SAE of appendicitis who completed study as planned. Five subjects had grade 3 AEs of self-limited injection site tenderness or pain. There were no grade 4 AEs or grade 3/4 labs. All dose cohorts achieved relevant plasma concentrations within 3 days with prolonged exposure in excess of protein-adjusted IC90 for both GSK744 and TMC278. TMC278 plasma concentrations were comparable to steady-state oral rilpivirine 25mg/day. Preliminary PK parameters following last dose (table):
[GSK744 LAP and TMC278 LA PK Parameters]
| ||Cohort 1
(Co-dosed Monthly)||Cohort 3
(Co-dosed Monthly)||Cohort 4
dose 1 (800mg) n=10|
Conclusion: Co-administration of injectable long-acting nanosuspensions of GSK744 and TMC278 was safe and generally well tolerated in healthy adults. Monthly or quarterly dosing regimens achieved clinically relevant plasma concentrations of GSK744 and TMC278. These data support clinical evaluation of GSK744 LAP+TMC278 LA antiretroviral regimens.
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