# Pharmacokinetics of islatravir in participants with moderate hepatic impairment

## TL;DR

This study examines how moderate liver impairment affects the body's processing of islatravir, an HIV drug, and finds only modest changes in drug levels.

## Contribution

The study provides new insights into islatravir pharmacokinetics in individuals with moderate hepatic impairment.

## Key findings

- Plasma islatravir and ISL-TP levels showed modest decreases in participants with moderate hepatic impairment.
- Plasma M4 levels were modestly increased, indicating increased metabolism via ADA in hepatic impairment.
- Islatravir was generally well tolerated in both healthy and hepatically impaired participants.

## Abstract

Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment of HIV-1 infection. People living with HIV are at risk of liver disease. ISL is metabolized by adenosine deaminase (ADA), which is expressed in the liver; thus, ISL pharmacokinetics (PK) may be affected by hepatic impairment. This study evaluated the effect of moderate hepatic impairment on ISL PK. This nonrandomized, open-label, phase 1 study (MK-8591-030) evaluated the effects of a single oral dose of ISL 60 mg in HIV-seronegative adults with moderate hepatic insufficiency (n = 6) and matched healthy adult participants (n = 6). Blood samples for plasma ISL and 4′-ethynyl-2-fluoro-2′deoxyinosine (M4) and peripheral blood mononuclear cell (PBMC) ISL-triphosphate (ISL-TP) were collected at multiple time points through 672 h, and safety was monitored throughout. Modest decreases in maximum measured concentration (Cmax) and area under the concentration-time curve (AUC) of plasma ISL and AUC of PBMC ISL-TP were observed in participants with moderate hepatic impairment versus matched healthy participants, while ISL-TP Cmax was relatively unchanged. In contrast, plasma M4 was modestly increased in the moderate hepatic impairment group, suggesting that hepatic impairment may result in increased metabolism of ISL to M4 via ADA. The clinical relevance of the overall modest changes in M4, ISL, and ISL-TP levels with moderate hepatic impairment will be contextualized once exposure response data from ongoing clinical studies are available to elucidate the thresholds for clinical efficiency. A single oral dose of ISL 60 mg was generally well tolerated in both groups.

This study is registered with Clinicaltrials.gov as NCT04515641.