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

• Published in: British journal of clinical pharmacology Vol. 89; no. 10; pp. 3067 - 3078
• Main Authors: Li, You, Yan, Bingqian, Guo, Siwei, Tian, Miaomei, Li, Yuan, Tong, Huan, Yu, Yunsong, Shao, Jing, Xin, Yuxia, Chen, Hui, Xu, Bing, Li, Xin
• Format: Journal Article
• Language: English
• Published: England 01.10.2023
• Subjects: pharmacokinetic/pharmacodynamic; YK-1169; pharmacokinetic; carbapenem-resistant Klebsiella pneumoniae; Monte Carlo simulation
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.15804

This 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. YK-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. Cefepime and avibactam both showed a linear pharmacokinetic profile. No accumulation was found after multiple doses. The cefepime C and AUC 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 C and AUC 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. YK-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.