First-in-human trial evaluates dosing of metallo-beta-lactamase inhibitor
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Key Takeaways:
- A metallo-beta-lactam inhibitor could help fight resistance to beta-lactam antibiotics.
- MK-3402 was found to be safe and well tolerated in first-in-human trials.
HOUSTON — IV treatment with a metallo-beta-lactam inhibitor could be an effective strategy to fight resistance to beta-lactam antibiotics, a researcher reported here.
Gillian Gillespie, MB, BChir, director of clinical pharmacology at Merk, presented findings at ASM Microbe from two first-in-human phase 1 trials of MK-3402.
“Metallo-beta-lactamases are this independent class of beta-lactamase enzymes that inactivate anti-beta-lactam antibacterials by hydrolysis,” Gillespie said during the presentation.
“This is a leading cause of gram-negative resistance, which is a major public health threat,” Gillespie said.
According to the CDC, more than 2.8 million antibiotic-resistant infections occur in the United States each year, roughly half of which are caused by gram-negative bacteria. There are a range of new treatment options in the pipeline to treat them.
MK-3402 is a small molecule metallo-beta-lactamase (MBL) inhibitor developed to stop MBL-producing pathogens in combination with a beta-lactamase A/C inhibitor and a beta-lactamase antibacterial agent to restore antibacterial activity, according to Merck, which is developing the drug.
Gillespie and colleagues tested the safety, tolerability and pharmacokinetics of both single and multiple IV doses of MK-3402 in two randomized, double-blind, placebo-controlled phase 1 studies in healthy adults.
For the first study, two alternating panels of participants received ascending single doses of the enzyme inhibitor of 25, 50, 100, 200, 400 or 600 mg or received a placebo across three treatment periods. A fourth period saw participants receive a split dose of 900 or 1100 mg across two infusions 6 hours apart.
In the second study, three sequential panels received ascending multiple doses of MK-3402 of 100 mg or placebo every 8 hours for 8 days, with another group receiving 200 or 350 mg or a placebo every 8 hours for 15 days.
According to the study, all treated study participants generally tolerated the treatment well, with no serious adverse events or discontinuations among participants.
“Putting it all together, these results are supportive of further clinical development of MK-3402,” Gillespie said.
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Gillespie G, et al. First-in-human studies of Mk-3402, a pan metallo-beta-lactamase inhibitor to combat antimicrobial resistance. Presented at: ASM Microbe, June 15-19, 2023; Houston.
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