Phase I dose-ascending, safety, and pharmacokinetics study of APC148, a novel metallo-β-lactamase inhibitor, in healthy volunteers

ABSTRACT APC148 is a novel metallo-β-lactamase inhibitor with broad activity against Ambler class B enzymes, including NDM, VIM, and IMP. It is being developed for patients with serious infections caused by multidrug-resistant, gram-negative bacteria. APC148 is combined with the broad-spectrum β-lactam antibiotic meropenem and the serine-β-lactamase inhibitor avibactam, which targets Ambler class A, C, and some class D (OXA-48-like) enzymes. In combination with meropenem and avibactam, APC148 demonstrated superior in vitro activity against a global, multidrug-resistant collection of Enterobacterales, showing its promising activity against β-lactamase-producing pathogens. In this randomized, placebo-controlled, first-in-human study, the safety, tolerability, and pharmacokinetics of APC148 were evaluated in healthy adults. Single doses ranging from 50 mg to 760 mg APC148 were administered intravenously over 3 h to 46 participants across six dose groups. APC148 was well-tolerated at all dose levels. All adverse events were of mild intensity, and no serious adverse events or adverse events leading to study or treatment discontinuation occurred. The pharmacokinetics of APC148 were dose-proportional, with low plasma clearance, low-to-moderate volume of distribution, and a mean plasma half-life of 2.6 h. APC148 is well-tolerated and represents a promising candidate in the fight against antibiotic-resistant bacteria. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT06360640 .