Abstract
Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1. The potential for islatravir to interact with commonly co-prescribed medications was studied in vitro. Elimination of islatravir is expected to be balanced between adenosine deaminase–mediated metabolism and renal excretion. Islatravir did not inhibit uridine diphosphate glucuronosyltransferase 1A1 or cytochrome p450 (CYP) enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, nor did it induce CYP1A2, 2B6, or 3A4. Islatravir did not inhibit hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 2, MRP3, or MRP4. Islatravir was neither a substrate nor a significant inhibitor of renal transporters organic anion transporter (OAT) 1, OAT3, OCT2, multidrug and toxin extrusion protein (MATE) 1, or MATE2K. Islatravir did not significantly inhibit P-glycoprotein and breast cancer resistance protein (BCRP); however, it was a substrate of BCRP, which is not expected to be of clinical significance. These findings suggest islatravir is unlikely to be the victim or perpetrator of drug-drug interactions with commonly co-prescribed medications, including statins, diuretics, anti-diabetic drugs, proton pump inhibitors, anticoagulants, benzodiazepines, and selective serotonin reuptake inhibitors.
Highlights
HIV-1 can be managed as a chronic illness with lifelong combination antiretroviral therapy (ART); the life expectancy of people living with HIV (PLWH) is approaching that of people without HIV, in high-income nations [1,2]
We describe in vitro studies conducted to characterize the distribution and metabolism of islatravir and to establish the potential for islatravir to interact with other drugs via major drug-metabolizing enzymes, and with transporters involved in clinically relevant drug interactions
The enzyme kinetics for recombinant human adenosine deaminase (ADA) showed a linear rate of M4 formation at concentrations of islatravir between 1 and 250 μM, which indicated that the ADA-catalyzed metabolism of islatravir to M4 is a high-capacity reaction, with a
Summary
HIV-1 can be managed as a chronic illness with lifelong combination antiretroviral therapy (ART); the life expectancy of people living with HIV (PLWH) is approaching that of people without HIV, in high-income nations [1,2]. In addition to ART, PLWH often require medications to treat their comorbidities, such as statins, diuretics, antidiabetic drugs, or benzodiazepines, which can lead to considerable polypharmacy and necessitates consideration of potential drug–drug interactions, adverse events, food restrictions, and complicated administration schedules [9,10,11]. The high frequency of drug interactions seen in PLWH receiving polypharmacy can result in adverse health outcomes and has typically required treatment modification or increased monitoring [12]. Viruses 2021, 13, 1566 polypharmacy can result in adverse health outcomes and has typically required treatment modification or increased monitoring [12] The high frequency of drug interactions seen in PLWH receiving polypharmacy can result in adverse health outcomes and has typically required treatment modification or increased monitoring [12]. 4.0/).
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