Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics Vaborbactam and Meropenem Alone and in Combination Following Single and Multiple Doses in Healthy Adult Subjects [PublishAheadOfPrint]

Meropenem-vaborbactam is a fixed combination of the novel β-lactamase inhibitor vaborbactam and the carbapenem antibiotic meropenem developed for the treatment of serious infections caused by drug-resistant gram-negative bacteria. The safety, tolerability and pharmacokinetics (PK) of vaborbactam and meropenem following single and multiple ascending doses of each study drug administered alone or combined were evaluated in 76 healthy adult subjects in a randomized, placebo-controlled, double-blind study. Subjects were enrolled in 1 of 5 dose cohorts (receiving 250—2000 mg vaborbactam and/or 1000—2000 mg meropenem) alone or in combination. No subjects discontinued the study due to adverse events (AEs), and no serious AEs were observed. The pharmacokinetics of meropenem and vaborbactam were similar when given alone or in combination; all evaluated plasma PK exposure measures (C_max, AUC_0-t, and AUC_0-inf) were similar for the study drugs alone versus combination, indicating no pharmacokinetic interaction between meropenem and vaborbactam. Across all treatments, 47 to 64% of an administered meropenem dose and 75 to 95% for vaborbactam was excreted unchanged in the urine over 48 h post dose. Meropenem and vaborbactam when given alone or in combination have similar pharmacokinetic properties, with no plasma or urine PK drug-drug interactions, and are well tolerated. These findings supported further clinical investigation of the combination product.

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