P-1167. Pharmacokinetics, Safety, and Tolerability of Funobactam in Combination with Imipenem/Cilastatin in Healthy Adult Elderly Male and Female Subjects

TL;DR

This study tested the safety and drug levels of funobactam combined with imipenem/cilastatin in elderly and young healthy volunteers.

Contribution

The novel β-lactamase inhibitor funobactam was evaluated in combination with imipenem/cilastatin in elderly and young healthy subjects.

Findings

Funobactam showed no significant age or gender effects on pharmacokinetics when baseline creatinine was considered.

The combination of imipenem/cilastatin and funobactam was safe and well tolerated in elderly subjects.

Pharmacokinetic parameters like Cmax and AUC varied across age groups but remained within expected ranges.

Abstract

Funobactam (formerly XNW4107) is a novel non-β-lactam diazabicyclooctane β-lactamase inhibitor with potent and selective direct activity against Ambler classes of A, C, D β–lactamases. Imipenem in combination with funobactam exhibits robust activity against carbapenem-resistant isolates of Enterobacterales, P. aeruginosa, and A. baumannii. This study evaluated pharmacokinetics (PK), safety, and tolerability of a single intravenous (IV) dose of imipenem 500 mg/ cilastatin 500 mg in combination with funobactam 250 mg in healthy adult elderly male and female subjects.

Eight subjects with 6 and 2 subjects randomized to active treatment or placebo, respectively, were enrolled into each of following 3 study cohorts: Cohort 1: Healthy young females≥ 18 to ≤ 45 years; Cohort 2: Healthy elderly males ≥ 65 years and Cohort 3: Healthy elderly females ≥ 65 years. Blood and urine samples were collected to determine funobactam, imipenem and cilastatin concentrations by LC-MS/MS method. The safety and tolerability were assessed by monitoring adverse events, ECGs, vital sign measurements, physical examinations, and clinical laboratory data.

The mean (SD) of maximum concentration (Cmax), area under plasma concentration curve from zero to infinity (AUC0-∞,) plasma clearance (CL), volume of distribution at terminal phase (Vz), half-life (t1/2) and renal clearance (CLr) for funobactam are shown in the table below:PKParameter (units)Cohort 1 (N=6)Cohort 2 (N=6)Cohort 3 (N=6)Cmax (µg/mL)16.3 (2.6)19.2 (6.52)18.2 (5.03)AUC0-inf (µg*h/mL)45.0 (4.27)68.2 (26.6)63.0 (13.5)CL (L/h)5.59 (0.51)4.08 (1.35)4.11 (0.84)VZ (L)20.2 (1.35)21.3 (6.43)18.6 (4.83)t1/2 (h)2.51 (0.11)3.66 (0.39)3.10 (0.46)CLr4.54 (1.47)2.97 (0.63)3.42 (0.73)

Overall, there was no age and gender effect on the PK of funobactam after taking the difference in baseline creatinine into consideration. The single 60-minute IV administration of imipenem 500 mg/cilastatin500 mg in combination with funobactam 500 mg was safe and well tolerated in healthy adult elderly male and female subjects.

All Authors: No reported disclosures