Population pharmacokinetic model library for isavuconazole: development and quality control

Isavuconazole is the first-line option for the treatment of invasive aspergillosis and mucormycosis. However, it has large pharmacokinetic (PK) variabilities, and suboptimal exposure is concerned. This study aimed to develop an isavuconazole population pharmacokinetic (PPK) library that contributes to model-informed precision dosing (MIPD) and dose optimization.

Following a systematic literature search and study inclusion, a library of isavuconazole PPK models was developed. The model characteristics and parameters estimated were extracted and compared. The AUC distributions at steady status across different models were compared, and the effects of covariates on PK parameters were analyzed. The model library was used to estimate target achievement with the PK/PD target of AUC/MIC 33 for Aspergillus through Monte Carlo simulations.

A total of 955 unduplicated records were initially identified from PubMed, Web of Science, and Embase. After screening and eligibility assessment, 14 studies were ultimately included in the model library. The quality scores of the included studies ranged from 35 to 45. The included PPK models had high reporting quality and covered a diversity of patients, with the two-compartment model being the most common. The total clearance of isavuconazole ranged from 1.33-5.34 L/h. Body weight, body surface area (BSA), body mass index (BMI), albumin levels, and liver function markers were the most common significant covariates, and their overall impact met the clinically significant criteria. The simulation results indicate that for a susceptive threshold of MIC 1 mg/L, most models (11/14) achieved PTA over 90%, while dose optimization may be required for critically ill patients, hematological patients and patients with abnormal covariates.

This study successfully developed a PPK library for isavuconazole, which would support the precision dosing of isavuconazole.