546. No Difference in MK-8591 and Doravirine Pharmacokinetics After Co-Administration

Abstract

BackgroundMK-8591 is a novel, highly potent, nucleoside reverse transcriptase translocation inhibitor (NRTTI) that is in development for the treatment of HIV-1 infection. MK-8591 is not expected to be a perpetrator or victim of drug–drug interactions (DDI), as it does not interact with renal or hepatic transporters, or with cytochrome P450 (CYP) enzymes in vitro. Doravirine (DOR), a novel non-nucleoside reverse transcriptase inhibitor (NNRTI), does not interact significantly with hepatic transporters or CYP enzymes but is metabolized by CYP3A4 in vitro. As MK-8591 is neither an inducer nor an inhibitor of CYP3A4, an interaction between MK-8591 and DOR was not expected. Currently, MK-8591 is being evaluated in a Phase 2 trial in combination with DOR.MethodsThe two-way interaction between MK-8591 and DOR was investigated in a double-blind, placebo-controlled, randomized, fixed-sequence, two-way drug–drug interaction study in 14 healthy adult subjects. Subjects received 5 days of 100 mg DOR or placebo QD, followed by 19 days of 2.25 mg MK-8591 or placebo QD, with 100 mg DOR or placebo co-administered QD for the last 5 days. Ten subjects received active drug and four received placebo throughout the trial.ResultsMultiple daily doses of MK-8591 and DOR alone and in combination were generally well tolerated. As noted in the table, the DOR area under the curve from time zero to 24 hours (AUC0-24), concentration at 24 hours (C24), and maximum concentration (Cmax) were similar with and without MK-8591, and the MK-8591 AUC0-24 and Cmax were similar with and without DOR.Table: Geometric Mean Ratio (GMR) with 90% Confidence Interval, Relative to Single Agent Administration (N = 10)DORMK-8591AUC0-241.13 [1.01, 1.28]1.06 [1.01, 1.12]C24†1.12 [0.95, 1.32]Cmax1.11 [0.99, 1.25]1.08 [0.91, 1.27] †C24 for parent MK-8591 is not related to efficacy and therefore not included.ConclusionNo clinically significant differences in PK were observed when MK-8591 and DOR were co-administered, which supports the Phase 2 co-dosing of MK-8591 and DOR. Consistent across trials, MK-8591 does not appear to interact with CYP3A4-mediated metabolism.Disclosures R. Matthews, Merck: Employee and Shareholder, Salary. D. Rudd, Merck: Employee and Shareholder, Salary. K. Fillgrove, Merck & Co., Inc.: Employee, Salary. S. Fox-Bosetti, Merck: Employee and Shareholder, Salary. V. Levine, Merck: Employee and Shareholder, Salary. S. Zhang, Merck & Co, Inc.: Employee, Salary. C. Tomek, Merck: Research Contractor, Research support and Salary. A. Stoch, Merck & Co, Inc.: Employee and Shareholder, Salary. M. Iwamoto, Merck & Co, Inc.:. Employee and Shareholder, Salary.