A Phase 1 Study to Evaluate the Drug Interaction Between Islatravir (MK-8591) and Doravirine in Adults Without HIV

Abstract

Background and Objectives Islatravir (MK-8591) is a novel nucleoside analogue in development for the treatment and prevention of HIV-1 infection. Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection. This study evaluated the pharmacokinetics, safety, and tolerability of islatravir and doravirine coadministration in a double-blind, placebo-controlled, randomized, fixed-sequence study. Methods Adult participants without HIV infection were administered oral doravirine 100 mg (n = 10) or placebo (n = 4) once daily (QD) for 5 days, immediately followed by oral islatravir 2.25 mg (n = 10) or placebo QD (n = 4) for 14 days; islatravir 2.25 mg and doravirine 100 mg QD, or placebo QD, were then coadministered for 5 days. Pharmacokinetic and safety data were collected. Results Doravirine geometric least-squares mean ratios (90% confidence intervals (CIs)) of (doravirine + islatravir)/doravirine for the area under the plasma drug concentration-time curve over 24 h (AUC 0-24h ), maximum plasma concentration (C max ), and plasma concentration at 24 h post-dose (C 24h ) were not meaningfully impacted. Islatravir geometric least-squares mean ratios (90% CI) of (islatravir + doravirine)/islatravir for AUC 0-24h and C max were both close to unity, 1.06 (1.01, 1.12) and 1.08 (0.91, 1.27), respectively. All study regimens were generally well tolerated. Conclusion These results indicate that coadministration of islatravir and doravirine had no clinically meaningful effect on the pharmacokinetics of either drug, and support further clinical investigation of islatravir in combination with doravirine for the treatment of HIV-1 infection.

Safety and Pharmacokinetics of Islatravir in Individuals with Severe Renal Insufficiency

“…Based on previous preclinical and clinical PK data, plasma islatravir and PBMC islatravir-TP levels were expected to increase in participants with severe RI relative to healthy control participants, considering islatravir undergoes renal clearance ( 6 , 12 , 13 , 23 , 25 ). The results of the current study suggest that plasma islatravir and M4 exposure were, in fact, higher in participants with severe RI, consistent with renal excretion as a relatively major factor in islatravir elimination ( 11 ).…”

Role of islatravir in HIV treatment and prevention: an update

“…This lack of inhibition and/or induction of major drug-metabolizing enzymes as well as common hepatic cotransporters (OATP1B1, OATP1B3, OCT1) allow for co-administration of other antiretrovirals with ISL. Furthermore, a phase 1b study analyzed the impact of ISL on the pharmacokinetic profile of the NNRTI doravirine in adults without HIV infection [40] and found that the pharmacokinetic of doravirine administered alone and in combination with ISL were comparable and that doravirine did not have a meaningful impact on the pharmacokinetic of ISL. Similarly, a study of 14 healthy subjects found no clinically meaningful interaction between ISL and the investigational NNRTI MK-8507 [41].…”