Tan Zhang 1, S. Matsumoto 2, L. Chen 1, M. Hasegawa 1, H. Okade 2, S. Shibasaki 2, H. Takano 2, Y. Igarashi 3, K. Matsumoto 3
1 Certara Strategic Consulting (, USA), 2 Meiji Seika Pharma Co.,Ltd (, Japan), 3 Keio University (, Japan)
Introduction: OP0595 (nacubactam) is a novel β-lactamase inhibitor with dual mechanisms of action: as an inhibitor of serine β-lactamases (classes A and C and some class D) and as an inhibitor of penicillin binding protein 2 [1]. OP0595 is expected to be effective against carbapenem-resistant Enterobacterales in combination with cefepime or aztreonam.
Objectives: This study aims to develop population pharmacokinetic (PK) models for OP0595, cefepime and aztreonam separately using data from Phase 1 to 3 clinical studies. Based on the developed models, this study estimates the probability of target attainment (PTA) of cefepime/OP0595 and aztreonam/OP0595 by renal function using preclinical PK/PD target values and calculates cumulative fractional response (CFR) using minimum inhibitory concentration (MIC) distribution surveillance data.
Methods: Population PK models for OP0595, cefepime and aztreonam were developed using plasma concentrations collected from subjects in eight clinical pharmacology studies and two Phase 3 clinical studies (OP0595: 737 subjects, cefepime: 353 subjects, and aztreonam: 195 subjects). Investigated covariates included body weight, age, sex, renal function (baseline creatinine clearance, CrCL in mL/min), ethnicity, concomitant medications, and disease. Based on the constructed population PK models, Monte Carlo simulations generated virtual patients with urinary tract infections, pulmonary infections, and intra-abdominal infections exhibiting varying renal functions and body weights. The joint probability of target attainment (joint PTA) of cefepime/OP0595 and aztreonam/OP0595 were calculated for each disease and renal function. The PK/PD target value for each drug (nacubactam: fAUC/MIC 6.0-6.5, cefepime: fT>MIC 50%, aztreonam: fT>MIC 40%) was set to achieve 1-log CFU (Colony Formulation Unit) reduction in a mouse thigh infection model infected with carbapenem-resistant Enterobacterales. CFR was estimated as the proportion of %PTA of each MIC according to the MIC distribution. The percentage of patients achieving joint PTA criteria and CFR should be ≥ 90%.
Results: For OP0595 and cefepime, 3-compartment models were developed, with clearance (CL) expressed as Hill’s equation using CrCL. Additional covariates identified included the effect of body weight on CL and the effects of body weight and disease status on central volume (Vc). Chinese was found to have an additional effect on cefepime CL, resulting in a 37.9% increase in CL in Chinese subjects. For aztreonam, a 3-compartment model was developed, with CL expressed as an exponential function using CrCL. Additional covariates identified included the effect of body weight on both CL and Vc. The constructed population PK models well reproduced plasma concentrations and were suitable to support PTA simulations. For both cefepime/OP0595 and aztreonam/OP0595, the maximum MIC achieving 90% PTA was found to be 8 mg/L across all diseases and renal function categories. This result was comparable to cefepime and aztreonam breakpoints as stated in the Clinical and Laboratory Standards Institute (CLSI) M100-Ed35. Furthermore, the overlaying PTA analysis results with global antimicrobial susceptibility distribution data for Enterobacterales collected from 2021 to 2023 revealed that almost all strains had MICs of 8 mg/L or lower. The CFR combined PTA and MIC distribution showed nearly 100% for Enterobacterales.
Conclusions: The developed population PK model well reflects plasma concentrations in patients for each drug, enabling its use for various purposes such as PTA analysis. The results of joint PTA analysis and the overlay with global surveillance data justify the administration of cefepime/OP0595 and aztreonam/OP0595 at the proposed dosage regimens, supporting their high clinical efficacy.
References:
[1] J Antimicrob Chemother. 2023 Apr 3;78(4):991-999. Pharm Res. 2023 Oct;40(10):2423-2431.
Reference: PAGE 34 (2026) Abstr 12043 [www.page-meeting.org/?abstract=12043]
Poster: Drug/Disease Modelling - Infection