Pharmacokinetics of YK‐1169 in healthy subjects and pharmacokinetic/pharmacodynamic analysis by Monte Carlo simulation

Abstract

ObjectiveThis study (NCT05588531) aimed to evaluate the safety and pharmacokinetics of cefepime‐avibactam (YK‐1169) in healthy Chinese subjects and explore the optimal regimen for treating carbapenem‐resistant Klebsiella pneumoniae (CRKP) based on the pharmacokinetic/pharmacodynamic evaluation.MethodsYK‐1169 single‐ascending doses (0.5, 1.25, 2.5 or 3.75 g, 2‐h infusion) and multiple doses (2.5 or 3.75 g every 8 h [q8h], 2‐h infusion) given for 7 days were evaluated in pharmacokinetic studies. Subjects were randomized to receive cefepime (2 g), avibactam (0.5 g) or YK‐1169 (2.5 g) to assess drug‐drug interactions. The minimum inhibitory concentrations (MICs) of YK‐1169 were determined by the broth microdilution method. Monte Carlo simulation was used to evaluate 10 different dose regimens.ResultsCefepime and avibactam both showed a linear pharmacokinetic profile. No accumulation was found after multiple doses. The cefepime Cmax,ss and AUC0‐∞,ss were 9.20 and 16.0 μg/mL, 407.2 and 659.45 μg·h/mL in the 2.5 and 3.75 g multiple‐dose groups, respectively. The avibactam Cmax,ss and AUC0‐∞,ss were 0.545 and 0.837 μg/mL, 53.31 and 79.55 μg·h/mL in the 2.5 and 3.75 g multiple‐dose groups, respectively. Cefepime and avibactam did not affect each other's pharmacokinetics. No serious adverse events occurred. All regimens achieved 90% probability of target attainment (PTA) goals when the MIC was ≤8 mg/L. The regimens of 2.5 (q8h, 2‐h infusion), 3.75 (q8h, 2‐, 3‐ and 4‐h infusions) and 7.5 g (24‐h continuous infusion) reached a 90% cumulative fraction of response.ConclusionYK‐1169 had good antibacterial activity against CRKP and could be an option for CRKP infections. The regimen of 2.5 g q8h intravenously guttae (ivgtt) 2 h should be considered in future clinical trials.