Population Pharmacokinetics and Pharmacodynamic Target Attainment of Isavuconazole against Aspergillus fumigatus and Aspergillus flavus in Adult Patients with Invasive Fungal Diseases: Should Therapeutic Drug Monitoring for Isavuconazole Be Considered as Mandatory as for the Other Mold-Active Azoles?

Pier Giorgio Cojutti,Carlo Tascini,Emanuela Sozio,Anna Candoni,Alessia Carnelutti,Renato Fanin,Federico Pea,Davide Lazzarotto

doi:10.3390/pharmaceutics13122099

Abstract

Isavuconazole is a newer broad-spectrum triazole approved for the treatment of invasive fungal disease. The objective of this study was to conduct a population pharmacokinetic and pharmacodynamic analysis of isavuconazole in a retrospective cohort of hospitalized patients. A nonlinear mixed-effect approach with Monte Carlo simulations was conducted to assess the probability of target attainment (PTA) of an area under the concentration–time curve (AUC24 h)/minimum inhibitory concentration (MIC) ratio of 33.4 (defined as efficacy threshold against A. fumigatus and A. flavus) associated with a maintenance dose (MD) of 100, 200 and 300 mg daily after loading. The cumulative fraction of response (CFR) against the EUCAST MIC distributions of A. fumigatus and A. flavus was calculated as well. The proportion of trough concentrations (Ctrough) exceeding a defined threshold of toxicity (>5.13 mg/L) was estimated. A total of 50 patients, with a median age of 61.5 years, provided 199 plasma isavuconazole concentrations. Invasive pulmonary aspergillosis was the prevalent type of infection and accounted for 80% (40/50) of cases. No clinical covariates were retained by the model. With the standard MD of 200 mg daily, CFRs were always ≥90% during the first two months of treatment. The risk of Ctrough < 1.0 mg/L was around 1%, and that of Ctrough > 5.13 mg/L was 27.7 and 39.2% at 28 and 60 days, respectively, due to isavuconazole accumulation over time. Our findings suggest that TDM for isavuconazole should not be considered as mandatory as for the other mold-active azoles voriconazole and posaconazole.

Highlights

Invasive fungal disease (IFD) represents one of the main causes of morbidity and mortality among immunocompromised patients [1]
All these aspects lead to the clinical perception that routine therapeutic drug monitoring (TDM) of isavuconazole may not be necessary in most circumstances, because clear evidence of the relationship between plasma concentrations and either efficacy or toxicity did not emerge in clinical trials [12]
The aim of this work was to conduct a population pharmacokinetic analysis of isavuconazole among hospitalized patients and a pharmacokinetic/pharmacodynamic study to assess the probability of target attainment with different dosing regimens of the pharmacodynamic threshold of efficacy against A. fumigatus and A. flavus

Summary

Introduction

Invasive fungal disease (IFD) represents one of the main causes of morbidity and mortality among immunocompromised patients [1]. The pharmacokinetics are linear up to 600 mg daily, the risk of drug-drug interactions is low, the tolerability is better than with voriconazole and there are no issues in terms of oral bioavailability compared to posaconazole [9,10,11]. All these aspects lead to the clinical perception that routine therapeutic drug monitoring (TDM) of isavuconazole may not be necessary in most circumstances, because clear evidence of the relationship between plasma concentrations and either efficacy or toxicity did not emerge in clinical trials [12]. This has been further supported by a recent report that showed a nearly identical distribution of the median isavuconazole concentration of 283 samples collected in the real-world clinical setting with that of 2458 samples collected in three phase

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Discussion

Conclusion