Low Doses of MK-8591 Provide High Inhibitory Quotients
MK-8591—a nucleoside reverse transcriptase translocation inhibitor (NRTTI)—has a high ratio of drug exposure to viral susceptibility among patients with wild-type and NRTTI-resistant HIV-1 infection, according to new data presented at the Conference on Retroviruses and Opportunistic Infections 2019.
Lead author Jay Gobler, from Merck & Co, presented the preliminary data from his phase 2 clinical trial of MK-8591 for the treatment of HIV-1 infection.
“We evaluated the [inhibitory quotients] of MK-8591-triphosphate in relation to other NRTTIs for wild-type and NRTTI-resistant HIV-1 to assess the likelihood of virologic response and barrier to resistance at clinically relevant doses,” Gobler and colleagues wrote.
After analyzing activated, uninfected human peripheral blood mononuclear cells after a 24-hour incubation period, the researchers summarized that the MK-8591-triphosphate IC50,IC for wild-type HIV-1 was more than 4-fold lower than any marketed NRTTI.
The inhibitory quotients were 85.3 for 0.25 mg/d dosing and 101 for 10 mg/w dosing. The quotients were proportionately higher for higher doses.
In addition, the researchers found that MK-8591 maintains higher inhibitory quotients against NRTTI-resistant viruses than those of TDF, TAF and 3TC with wild-type virus.
“The [inhibitory quotients] of MK-8591 for both [wild-type] and NRTTI-resistant HIV-1 at low [once daily] and [once weekly] doses are substantially higher than those of any NRTTIs approved for HIV treatment,” the researchers concluded.
“Coupled with the long intracellular half-life of the MK-8591-TP, these [inhibitory quotients] suggest the opportunity for multiple low dosing options with the potential for a high barrier to the development of resistance.”
—Amanda Balbi
Reference:
Grobler J, Fillgrove K, Hazuda D, et al. MK-8591 potency and PK provide high inhibitory quotients at low doses QD and QW. Paper presented at: Conference on Retroviruses and Opportunistic Infections 2019; March 4-7, 2019; Seattle, WA. http://www.croiconference.org/sessions/mk-8591-potency-and-pk-provide-high-inhibitory-quotients-low-doses-qd-and-qw. Accessed March 8, 2019.