Isavuconazole therapeutic drug monitoring during long-term treatment for chronic pulmonary aspergillosis

Objectives: Isavuconazole is the newest triazole antifungal and displays a favourable pharmacokinetics and safety profile. Less is known about its long-term use in immunocompetent hosts. Methods: We performed a retrospective service evaluation of isavuconazole therapeutic drug monitoring in patients with chronic pulmonary aspergillosis . Adverse events (AEs) and dose adjustments made during routine clinical practice were recorded, and AEs were classified based on Common Terminology Criteria for Adverse Events v5.0. Results: Forty-five patients (mean age 64 years) had 285 isavuconazole blood drug levels measured (mean level of 4.1 mg/L). One hundred and seventeen (41%) measurements were performed on patients on 100mg daily dose instead of 200mg and all had a blood level >1 mg/L. Age (p=0.012) and daily dose of 200mg vs. 100mg (p=0.02) were independent predictors of a level >6 mg/L. Adverse events (AEs) were recorded in 25 (56%) patients. Mean drug level at the first measurement was 5.5 ±2 mg/L in patients reporting AEs vs 4.2 ±1.7 mg/L in those not reporting AEs (p=0.032). The cut-off threshold best predictive of an AE was 4.6 mg/L (AUC=0.710). Sixteen (36%) patients discontinued isavuconazole due to AEs. Twenty-six patients (58%) continued on isavuconazole beyond six months. Asthma (p=0.022) and a daily dose of 200mg vs. 100mg (p=0.048) were associated with AE Grade 2 or higher. Conclusions: A reduced daily dose (100 mg vs. 200 mg) of isavuconazole resulted in satisfactory drug levels in a substantial number of patients. It was better tolerated and enabled continuation of therapy for prolonged periods.