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

• Published in: Clinical drug investigation 2021-07, Vol.41 (7), p.629-638
• Main Authors: Matthews, Randolph P., Jackson Rudd, Deanne, Fillgrove, Kerry L., Zhang, Saijuan, Tomek, Charles, Stoch, S. Aubrey, Iwamoto, Marian
• Format: Article
• Language: English
• Subjects: Adenosine; Administration, Oral; Adult; Adults; Antiretroviral drugs; Area Under Curve; Body mass index; Deoxyadenosines - administration & dosage; Deoxyadenosines - adverse effects; Deoxyadenosines - blood; Deoxyadenosines - pharmacokinetics; Double-Blind Method; Drug Administration Schedule; Drug dosages; Drug Interactions; Drug resistance; Female; Half-Life; HIV; Human immunodeficiency virus; Humans; Infections; Internal Medicine; Least-Squares Analysis; Male; Medicine; Medicine & Public Health; Middle Aged; Original; Original Research Article; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Placebo Effect; Plasma; Pyridones - administration & dosage; Pyridones - adverse effects; Pyridones - blood; Pyridones - pharmacokinetics; ROC Curve; Sleepiness; Substance abuse treatment; Triazoles - administration & dosage; Triazoles - adverse effects; Triazoles - blood; Triazoles - pharmacokinetics; Young Adult
• ISSN: 1173-2563; 1179-1918
• DOI: 10.1007/s40261-021-01046-1

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.