Infectious Disease · Medical Literature
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 TRIALSThis study is registered with ClinicalTrials.gov as NCT06360640.
Clinical relevance
Is APC148, a novel metallo-β-lactamase inhibitor intended for use in combination with meropenem and avibactam, safe, well-tolerated, and characterized by acceptable pharmacokinetics when administered as single escalating intravenous doses to healthy adults? __SNAPSHOT__ {"studyDesign":"Phase I, randomized, placebo-controlled, single ascending dose, first-in-human study","setting":"Not reported (clinical trial unit setting implied; institutional country not specified in abstract)","sampleSize":"n=46, across six dose groups; active-to-placebo allocation ratio not reported","population":"Healthy adult volunteers; specific age range, sex distribution, weight, and renal function criteria not reported in the abstract","intervention":"APC148 administered intravenously over 3 hours as single doses ranging from 50 mg to 760 mg across six ascending dose cohorts","comparator":"Placebo (randomized, placebo-controlled design stated; exact placebo composition not reported)","primaryOutcome":"Safety and tolerability of APC148 (adverse event frequency and severity); pharmacokinetic characterization as co-primary or secondary outcome (complete PK parameter results truncated in the available abstract)","followUp":"Not reported (single-dose study; duration of post-dose observation not specified in the available abstract)","fundingSource":"Not reported in the available abstract; principal investigators are affiliated with an industry-linked development program (APC series compounds)"}
Key findings
APC148 was reported to be well-tolerated across all six dose levels (50 mg to 760 mg IV). All adverse events were of mild intensity. No serious adverse events occurred, and no participant discontinued the study or treatment due to an adverse event. Specific pharmacokinetic parameters (Cmax, AUC, half-life, volume of distribution, clearance, degree of dose-proportionality) are not fully reported in the available abstract, as the abstract appears to be truncated. No quantitative effect sizes, confidence intervals, p-values, or NNT/NNH values are derivable from the available text. In preclinical and in vitro contexts reported by the same research group, the triple combination of APC148 + meropenem + avibactam demonstrated superior in vitro activity against a global MDR Enterobacterales collection including NDM-, VIM-, and IMP-producing isolates, achieving a MIC90 of 0.12 µg/mL (source: related bioRxiv preprint by same group; not from this Phase I study).
Practice implications
This first-in-human study establishes an early human safety and tolerability signal for APC148, demonstrating that single IV doses up to 760 mg were free of serious adverse events and produced only mild adverse effects in healthy volunteers. The study does not establish efficacy, optimal dosing regimens, PK/PD target attainment in infected patients, safety in renally or hepatically impaired individuals, drug-drug interaction profiles when combined with meropenem and avibactam, or outcomes in any patient population. Findings are applicable only to healthy adults and cannot be generalized to the immunocompromised, critically ill, elderly, or those with organ dysfunction who represent the intended clinical population. The abstract is truncated; complete pharmacokinetic data (including dose-proportionality, half-life, and exposure benchmarks against preclinical PK/PD targets) are not available for evaluation. Confirmation of PK adequacy for combination therapy requires review of the full publication. NOTE: Only the abstract was available for this summary; full quantitative PK results and statistical detail could not be assessed. __LIMITATIONS__ Abstract is truncated; complete pharmacokinetic results and statistical analyses are unavailable for critical appraisal.,Phase I study in healthy volunteers only; no patients with MBL-producing infections enrolled; efficacy cannot be inferred.,Small sample size (n=46 across six cohorts) limits detection of uncommon adverse events.,Single ascending dose design only; multiple-dose, steady-state PK, and safety data in the context of co-administration with meropenem and avibactam are not reported.,Key at-risk populations (renally impaired, critically ill, immunocompromised, elderly) were not represented.,Funding source not disclosed in abstract; potential for industry influence on study design and reporting cannot be assessed.,Short observation period inherent to a single-dose Phase I design; delayed or cumulative toxicity cannot be detected.,No pharmacodynamic or microbiological endpoints included in this Phase I trial.,In vitro superiority data cited in the abstract are from a separate preclinical study and do not establish clinical benefit. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This first-in-human, randomized, placebo-controlled Phase I study demonstrates that single IV doses of APC148 from 50 mg to 760 mg were well-tolerated in healthy adults, with only mild adverse events and no serious or treatment-limiting safety signals. Pharmacokinetic characterization was performed but full results are not available in the truncated abstract. These data support advancement of APC148 into multiple-dose and drug-combination studies, but efficacy, optimal dosing, and safety in target patient populations remain to be established.