Pharmacokinetic/Pharmacodynamic Analysis of Isavuconazole Against Aspergillus spp. and Candida spp. in Healthy Subjects and Patients With Hepatic or Renal Impairment by Monte Carlo Simulation

Abstract

The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study is to evaluate the efficacy of various isavuconazole dosing regimens for healthy individuals and patients with hepatic or renal impairment against Aspergillus spp. and Candida spp. Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamics (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (AUC/MIC) targets of isavuconazole. A clinically recommended dosage regimen of isavuconazole (200 mg qd) obtained high cumulative fraction of response values of > 90% for all subjects against A. fumigatus, A. flavus, A. nidulans, A. terreus, A. versicolor, C. parapsilosis and C. tropicalis. For patients with mild or moderate hepatic impairment, the dosage should be halved only when treating invasive fungal infections caused by C. albicans, C. parapsilosis or C. tropicalis. However, dose adjustment is unlikely to be required in mild to severe renal impairment patients because all cumulative fraction of response values were similar to those of comparing with healthy subjects. Notably, all isavuconazole dosing regimens were not effective against C. glabrata and C. krusei in all subjects. These PK/PD-based simulations rationalize and optimize the dosage regimens of isavuconazole for healthy individuals and patients with hepatic or renal impairment against Aspergillus spp. and Candida spp.

Optimization of Dosage Regimen of Rezafungin against <i>Candida spp. </i>Based on Pharmacokinetic/Pharmacodynamic Analysis

“…For example, platinum isavuconazole had a max CFR value of 80.68% under different dosing regimens [15]. Isavuconazole had a max CFR value of 62.70% under different dosing regimens [16]. In this study, Monte Carlo simulation analysis showed that rezafungin in healthy people could obtain good results when the dosage is 50 mg, which provides a basis for subsequent clinical research and application.…”

Pre-Existing Liver Disease and Toxicity of Antifungals

“…In a recently published PK/PD study, Zheng et al examined the efficacy of various isavuconazole dosing regimens for healthy individuals and patients with renal and hepatic impairment, namely Child-Pugh Class A or B cirrhosis, against Aspergillus spp. and other fungi [134]. The Monte Carlo simulation was used in each scenario to calculate target attainment and cumulative fractions of response probabilities.…”

“…The clinically recommended dose of 200 mg isavuconazole per day was effective for all individuals against A. fumigatus , A. flavus , A. nidulans , A. terreus , and A. versicolor . [134].…”