Echinocandins Pharmacokinetics: A Comprehensive Review of Micafungin, Caspofungin, Anidulafungin, and Rezafungin Population Pharmacokinetic Models and Dose Optimization in Special Populations.

Abstract

In recent years, many population pharmacokinetic (popPK) models have been developed for echinocandins to better understand the pharmacokinetics (PK) of these antifungals. This comprehensive review aimed to summarize popPK models of echinocandins (micafungin, caspofungin, anidulafungin, and rezafungin), by focusing on dosage optimization to maximize the probability of attaining the PK/PD target proposed in special populations. A search in PubMed, Embase, Web of Science, and Scopus, supplemented by the bibliography of relevant articles, was conducted from inception to March 2024, including both observational and prospective trials. A total of 1126 articles were identified, 47 of them were included in the review (22 for micafungin, 13 for caspofungin, 9 for anidulafungin, and 3 for rezafungin). A two-compartment model was more frequently used to describe the PK parameters of echinocandin (78.7% of developed models), although more complex structural models with three and four compartments have also been developed. The covariates to estimate the PK parameters such as clearance (CL) and volume of distribution (V_d) differed between models. Weight total (WT) was the most frequently reported to be a significant predictor for both parameters, especially for estimating the CL in pediatrics. The PD parameter most widely reported assessing the drug exposure-efficacy relationship was the area under the concentration-time curve to minimum inhibitory concentration (MIC) ratio (AUC_0-24/MIC) with different targets proposed for each echinocandin. In certain populations such as patients that are critically ill, obese, receiving extracorporeal membrane oxygenation (ECMO) and/or continuous renal replacement therapy (CRRT), or pediatric patients and/or patients with cancer or that are immunocompromised, the fixed dosing strategies recommended in the drug prescribing information may not reach the PK/PD target. For these populations, different strategies have been proposed, such as a dosing regimen based on body weight or increasing the loading and/or maintenance dose. Despite echinocandins' favorable safety profile and predictable PK, certain groups at risk of suboptimal drug exposure can benefit from therapeutic drug monitoring (TDM) to prevent clinical failures. Numerous popPK models of echinocandins have been developed. However, an external validation of the suggested dosing regimens in conjunction with an analysis of population subgroups should be conducted before implementing a popPK model in clinical practice.