Model-Informed Drug Development, Pharmacokinetic/Pharmacodynamic Cutoff Value Determination, and Antibacterial Efficacy of Benapenem against Enterobacteriaceae
| Autor: | Wei Zhong, Isabelle H. S. Kuan, Zi-Sheng Kang, Xi-Wei Ji, Yun Li, Xiao Zhu, Yuan Lv, Xi-Ping Yang, Feng Xue |
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| Rok vydání: | 2020 |
| Předmět: |
Pharmacology
0303 health sciences Carbapenem biology 030306 microbiology business.industry Liter biology.organism_classification 030226 pharmacology & pharmacy Enterobacteriaceae 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Infectious Diseases chemistry Pharmacokinetics Pharmacodynamics medicine Cutoff Pharmacology (medical) Dosing business Ertapenem medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 64 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | Benapenem is a novel carbapenem. The objective of this study was to determine the pharmacokinetic (PK)/pharmacodynamic (PD) cutoff values and evaluate the optimal administration regimens of benapenem for the treatment of bacterial infections via PK/PD modeling and simulation. Ertapenem was used as a control. Infected mice received an intravenous (i.v.) injection of benapenem or ertapenem of 14.6, 58.4, or 233.6 mg/kg of body weight, and the PK/PD profiles were evaluated. The MICs were determined by using a 2-fold agar dilution method. Mathematical models were developed to characterize the pharmacokinetic profile of benapenem in humans and mice. Monte Carlo simulations were employed to determine the cutoff values and the appropriate benapenem dosing regimens for the treatment of infections caused by clinical isolates of Enterobacteriaceae Two 2-compartment models were developed to describe the PK profiles of benapenem in humans and mice. A two-site binding model was applied to fit the protein binding in mouse plasma. Through correlation analysis, the percentage of the time that the free drug concentration remains above the MIC (%fT >MIC) was determined to be the indicator of efficacy. Results from the simulation showed that the probability of target attainment (PTA) against the tested isolates was over 90% with the dosing regimens studied. The PK/PD cutoff value of benapenem was 1 mg/liter at a %fT >MIC of 60% when given at a dose of 1,000 mg/day by i.v. drip for 0.5 h. The established model provides a better understanding of the pharmacological properties of benapenem for the treatment of Enterobacteriaceae infections. The proposed PK/PD cutoff value suggests that benapenem is a promising antibacterial against the Enterobacteriaceae The cutoff value of 1 mg/liter may be a useful guide for the clinical use of benapenem and for surveillance for benapenem resistance. |
| Databáze: | OpenAIRE |
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