546. No difference in MK-8591 and doravirine pharmacokinetics after co-administration
Session: Poster Abstract Session: HIV: Antiretroviral Therapy
Thursday, October 4, 2018
Room: S Poster Hall
Background: MK-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.

Methods: The two-way interaction between MK-8591 and DOR was investigated in a double-blind, placebo-controlled, randomized, fixed-sequence, 2-way drug-drug interaction study in 14 healthy adult subjects. Subjects received five 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 five days. Ten subjects received active drug and four received placebo throughout the trial.

Results: Multiple 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)

DOR

MK-8591

AUC0-24

1.13 [1.01, 1.28]

1.06 [1.01, 1.12]

C24

1.12 [0.95, 1.32]

Cmax

1.11 [0.99, 1.25]

1.08 [0.91, 1.27]

C24 for parent MK-8591 is not related to efficacy and therefore not included.

Conclusion: No 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.

Randolph Matthews, MD, PhD1, Deanne Rudd, PhD2, Kerry Fillgrove, PhD2, Sabrina Fox-Bosetti, MPH3, Vanessa Levine, MS3, Sandra Zhang, PhD3, Charles Tomek, MD4, Aubrey Stoch, MD3 and Marian Iwamoto, MD, PhD3, (1)Merck & Co., Inc., North Wales, PA, (2)Merck & Co., Inc., West Point, PA, (3)Merck & Co., Inc., Rahway, NJ, (4)Celerion, Lincoln, NE

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 .

Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 3rd with the exception of research findings presented at the IDWeek press conferences.