Dataset Information

Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV.

ABSTRACT: Islatravir (MK-8591) is a nucleoside analogue in development for the treatment and prevention of HIV-1. Two phase 1 trials were conducted during initial evaluation of islatravir: rising single doses (Study 1) and rising multiple doses (Study 2) of oral islatravir in male and female participants without HIV (aged 18-60 years). Safety, tolerability, and pharmacokinetics of islatravir (plasma) and islatravir-triphosphate (peripheral blood mononuclear cells) were assessed. In Study 1, 24 participants, assigned to 1 of 3 panels, received alternating single doses of islatravir in a fasted state from 5 mg to 400 mg, or placebo, over 3 dosing periods; a 30 mg dose was additionally assessed following a high-fat meal. In Study 2, 8 participants per dose received 3 once-weekly doses of 10, 30, or 100 mg islatravir or placebo in a fasted state. For each panel in both trials, 6 participants received active drug and 2 received placebo. Islatravir was generally well-tolerated, with no serious adverse events or discontinuations due to adverse events. Islatravir was rapidly absorbed (median time to maximum plasma concentration 0.5 hours); plasma half-life was 49-61 h; intracellular islatravir-triphosphate half-life was 118-171 h. Plasma exposure increased in an approximately dose-proportional manner; there was no meaningful food effect. There was a modest degree of intracellular islatravir-triphosphate accumulation after multiple weekly dosing. After single oral doses of islatravir greater than or equal to 5 mg, intracellular islatravir-triphosphate levels were comparable to levels associated with efficacy in preclinical studies. These results warrant continued clinical investigation of islatravir.

SUBMITTER: Matthews RP

PROVIDER: S-EPMC8504818 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV.

Matthews Randolph P RP Ankrom Wendy W Friedman Evan E Jackson Rudd Deanne D Liu Yang Y Mogg Robin R Panebianco Deborah D De Lepeleire Inge I Petkova Magdalena M Grobler Jay A JA Stoch Selwyn Aubrey SA Iwamoto Marian M

Clinical and translational science 20210831 5

Islatravir (MK-8591) is a nucleoside analogue in development for the treatment and prevention of HIV-1. Two phase 1 trials were conducted during initial evaluation of islatravir: rising single doses (Study 1) and rising multiple doses (Study 2) of oral islatravir in male and female participants without HIV (aged 18-60 years). Safety, tolerability, and pharmacokinetics of islatravir (plasma) and islatravir-triphosphate (peripheral blood mononuclear cells) were assessed. In Study 1, 24 participant ...[more]

PMID: 34463432

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Project description:BackgroundOral drug formulations have several advantages compared to intravenous formulation. Apart from patient convenience and favorable pharmacoeconomics, they offer the possibility of frequent drug administration at home. In this study, we present a new oral irinotecan formulation designed as an enteric coated immediate release tablet which in pre-clinical studies has shown good exposure with low variability.MethodsA phase I, dose escalating study to assess safety, tolerability, pharmacokinetics and efficacy of an oral irinotecan formulation and to establish the maximum tolerated dose (MTD). Each treatment cycle was once-daily irinotecan for 14 days followed by 1 week rest.Results25 patients were included across four cohorts; 3 patients were included in cohort 1 (20 mg/m2), 7 patients were included in cohort 2 (30 mg/m2), 3 patients were included in cohort 3 (25 mg/m2) and 12 patients were included in cohort 4 (21 mg/m2). Median age was 67 years, 52% were performance status (PS) 0 while 48% were PS 1. Median number of prior therapies was 3 (range 1-6). MTD was established at 21 mg/m2. No responses were observed. Nine patients (36%) had stable disease (SD), lasting median 19 weeks (range 7-45 weeks). Among these five patients had previously received irinotecan. No grade 3/4 hematologic toxicities were reported. Totally six patients experienced grade 1/2 anemia, three patients had grade 1/2 leucopenia and 1 patient had grade 1 thrombocytopenia. Most common non-hematological grade 1 and 2 adverse events were nausea, fatigue, diarrhea, vomiting and cholinergic syndrome. Grade 3 toxicities included diarrhea, fatigue, nausea and vomiting, no grade 4 events were reported. PK data showed consistent daily exposures during treatment at days 1 and 14 and no drug accumulation. SN-38 interpatient variability was in the same range as after infusion.ConclusionsOral irinotecan was generally well tolerated; side effects were manageable and similar in type to those observed with intravenous irinotecan. Hematological toxicities were few and only grade 1/2. In this heavily pre-treated patient population, oral irinotecan demonstrated activity even among patients previously treated with irinotecan.

Dataset Information

Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV.

Publications

Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV.

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