No pharmacokinetic interaction between novel NNRTI MK-8507 and Islatravir


BACKGROUND: The combination of MK-8507 and islatravir (ISL) is currently in Phase 2 development as a once weekly (QW), complete, oral regimen for treatment of HIV-1 infection. MK-8507 is a potent HIV-1 non-nucleoside reverse transcriptase inhibitor with a t1/2 of 70 hrs. Islatravir (ISL) is a potent, HIV-1 nucleoside reverse transcriptase translocation inhibitor with an intracellular t1/2 of the active triphosphorylated moiety of ~190 hrs. The antiviral activity and long t1/2 make these drugs suitable for QW administration. Neither MK-8507 nor ISL inhibit or induce major CYP enzymes or transporters, and the two drugs are not expected to interact. This clinical study evaluated the two-way drug-drug interaction (DDI) of MK-8507 and ISL to support their combined use in Phase 2.
METHODS: This was an open-label, fixed-sequence DDI study in healthy men and women of nonchildbearing potential. A single dose of 20 mg ISL was given followed by a 7-day washout. MK-8507, 400 mg, was then dosed once weekly for 3 weeks; a single dose of 20 mg ISL was given concomitantly with the 3rd dose of MK-8507. PK samples were collected for evaluation of ISL following both doses and for MK-8507 following the second and third doses.
RESULTS: Fourteen participants (5 female) aged 29-59 were enrolled; 13 completed. The PK of MK-8507 and ISL were not meaningfully altered by co-administration. The geometric mean ratios (GMRs) (90% confidence intervals (CIs) for MK-8507 AUC0-168, Cmax and Ctrough given with ISL compared to alone were 1.07 (1.04, 1.11), 1.06 (0.98, 1.15), and 1.08 (1.04, 1.13), respectively; for ISL the GMRs (90% CI) for AUC0-inf and Cmax given with MK-8507 compared to alone were 1.24 (1.14, 1.35) and 1.19 (1.06, 1.33), respectively. The small increase in MK-8507 and ISL exposures is not clinically meaningful. The small increase in MK-8507 PK can be attributed in part to accumulation after weekly dosing as evidenced in the predose concentrations observed prior to co-administration. Co-administration of the two drugs was generally well tolerated.
CONCLUSIONS: There was no clinically meaningful interaction between MK-8507 and ISL, supporting further clinical development of this 2-drug, once weekly regimen.