Whole-body physiology-based pharmacokinetics of caspofungin for general patients, intensive care unit patients and hepatic insufficiency patients

• Published in: Acta pharmacologica Sinica Vol. 39; no. 9; pp. 1533 - 1543
• Main Authors: Yang, Qian-ting, Zhai, Ya-jing, Chen, Lu, Zhang, Tao, Yan, Yan, Meng, Ti, Liu, Lei-chao, Chen, Li-mei, Wang, Xue, Dong, Ya-lin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2018; Nature Publishing Group
• Subjects: Adult; Antifungal agents; Antifungal Agents - administration & dosage; Antifungal Agents - pharmacokinetics; Azoles; Biomedical and Life Sciences; Biomedicine; Body weight; Candidiasis; Caspofungin; Caspofungin - administration & dosage; Caspofungin - pharmacokinetics; Clinical trials; Computer simulation; Echinocandins; Fungicides; Hepatic Insufficiency - metabolism; Heterocyclic compounds; Humans; Immunology; Intensive care; Intensive Care Units; Internal Medicine; Liver; Male; Medical Microbiology; Models, Biological; Monte Carlo Method; Monte Carlo simulation; Pharmacokinetics; Pharmacology/Toxicology; Physiology; Vaccine; Young Adult; whole-body physiology-based pharmacokinetics model; antifungal agent; hepatic insuffciency; intensive care unit; cumulative fraction of response; caspofungin
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2017.176

Caspofungin is an echinocandin antifungal agent licensed as a first-line therapy for invasive candidiasis in patients with moderate to severe illness or recent exposure to azoles. In this study we developed a whole-body physiology-based pharmacokinetics (WB-PBPK) model to predict the pharmacokinetics (PK) of caspofungin, and combined with Monte Carlo simulation (MCS) to optimize clinical dosage regimens of caspofungin in different kinds of patients. A WB-PBPK model of caspofungin was built and validated with raw data from 4 previous trials of general patients, intensive care unit (ICU) patients with Child-Pugh B, ICU patients on continuous renal replacement therapy, mild and moderate hepatic insuffciency (HI) patients. MCS was used to optimize clinical dosage regimens of caspofungin in these patients. A cumulative fraction of response (CFR) value of ≥90% was considered to be the minimum for achieving optimal empirical therapy. The simulated results of the WB-PBPK model were in good agreement with observed values of all trials. For general and ICU patients with caspofungin 70/50 mg, AUC and Cmax were decreased with the increase of body weight (BW) and showed great variation. MCS showed all general patients achieved CFR≥90% regardless of BW. But not all ICU patients with higher BW (≥70 kg) could achieve CFR≥90%. Compared with standard dosage regimens in general patients, caspofungin 70/35 mg in ICU patients with Child-Pugh B achieved significantly decreased AUC and Cmax, but obtained similar AUC and Cmax in moderate HI patients with Child-Pugh B. The WB-PBPK model of caspofungin is able to predict PK of all populations correctly. The combined WB-PBPK model with MCS can successfully optimize clinical dosage regimens of caspofungin in all patient populations.