Islatravir (ISL, MK-8591) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) in development for the treatment and prevention of HIV-1 infection. We previously showed that ISL + doravirine (DOR) was effective in maintaining viral suppression through week 96 and was well-tolerated. Here we present a detailed safety analysis of those results. [blocked by paywall]
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.
There is a large gap in ISL concentration between the pharmacological dose to proximal tubular cells and the clinical dose. ISL is unlikely to be taken up via OAT1 or OAT3; therefore, OAT1 and OAT3 may not be involved in the injury to tubular cells. Present data strongly suggests that ISL is not toxic to
Treatment regimens containing islatravir and doravirine showed antiviral efficacy and were well tolerated regardless of dose. Doravirine in combination with islatravir has the potential to be a potent two-drug regimen that warrants further clinical development.
The unnatural, alkyne-containing nucleoside analog islatravir (MK-8591) is synthetically accessed through a biocatalytic cascade starting from 2-ethynylglycerol as a building block. Herein, we describe the development of an efficient synthesis of this building block including the initial route, route scouting and final process development.
Development of an Efficient Route to 2-Ethynylglycerol for the Synthesis of Islatravir Read More »
Doravirine showed a more robust resistance profile compared with other NNRTIs. The long intracellular half-life of islatravir and delayed acquisition of resistance in dual selections provide an opportunity for long-acting treatment options
An evolved GOase variant was recently shown to catalyze a desymmetrizing oxidation as the first enzymatic step in the biocatalytic synthesis of islatravir. Horseradish peroxidase (HRP) is required to activate the GOase, introducing cost and protein burden to the process.
Islatravir (MK-8591), a highly potent nucleoside reverse transcriptase translocation inhibitor, is being developed to stem the spread of global HIV infections. With efficacy at sub-milligram doses, islatravir requires a robust crystallization method for consistent particle size to meet content uniformity requirements in a tablet. Herein, we outline the development of two robust crystallization methods that
Interim PK analysis shows ISL-triphosphate trough concentrations following either 60 mg or 120 mg monthly doses were all above the pre-specified PK threshold for HIV-1 prophylaxis of 0.05 pmol/[10 (6) PBMCs. Preliminary PK analysis of biopsied tissues suggest rapid, sustained and adequate distribution of ISL to sampled tissues. ISL PK exhibited linear dose proportionality (Figure
Here we disclose the development of bioelectrocatalytic aerobic oxidation of alcohols under mild conditions, using a water-soluble ferrocene derivative as the electrocatalyst. Mechanistic insights into the electrochemical activation of GOase were gathered by interrogating the enzyme redox properties and the electron transfer rates between GOase and the electrochemically generated oxidants.
