Safety and pharmacokinetics of isavuconazole as antifungal prophylaxis in acute myeloid leukemia patients with neutropenia: results of a phase 2, dose escalation study

Abstract

Isavuconazole is a novel broad-spectrum triazole antifungal agent. This open-label dose escalation study assessed the safety and pharmacokinetics of intravenous isavuconazole prophylaxis in patients with acute myeloid leukemia who had undergone chemotherapy and had preexisting/expected neutropenia. Twenty-four patients were enrolled, and 20 patients completed the study. The patients in the low-dose cohort (n = 11) received isavuconazole loading doses on day 1 (400/200/200 mg, 6 h apart) and day 2 (200/200 mg, 12 h apart), followed by once-daily maintenance dosing (200 mg) on days 3 to 28. The loading and maintenance doses were doubled in the high-dose cohort (n = 12). The mean ± standard deviation plasma isavuconazole areas under the concentration-time curves for the dosing period on day 7 were 60.1 ± 22.3 μg · h/ml and 113.1 ± 19.6 μg · h/ml for the patients in the low-dose and high-dose cohorts, respectively. The adverse events in five patients in the low-dose cohort and in eight patients in the high-dose cohort were considered to be drug related. Most were mild to moderate in severity, and the most common adverse events were headache and rash (n = 3 each). One patient in the high-dose cohort experienced a serious adverse event (unrelated to isavuconazole treatment), and two patients each in the low-dose and high-dose cohorts discontinued the study due to adverse events. Of the 20 patients who completed the study, 18 were classified as a treatment success. In summary, the results of this analysis support the safety and tolerability of isavuconazole administered at 200 mg and 400 mg once-daily as prophylaxis in immunosuppressed patients at high risk of fungal infections. (This study is registered at ClinicalTrials.gov under registration number NCT00413439.).

FIG 1

Patient flow diagram. Two patients in the low-dose cohort and four patients in the high-dose cohort prematurely discontinued study treatment but completed the study (i.e., attended remaining scheduled visits and underwent prespecified testing procedures). The study began with 12 patients (of the 24 enrolled) in the low-dose cohort, followed by a second set of 12 patients in the high-dose cohort; none of the 12 patients in the high-dose cohort had participated in the low-dose phase of the study.

FIG 2

Mean ± standard deviation (SD) isavuconazole plasma concentration-time profiles after intravenous administration of isavuconazole on days 1 (A) and 7 (B) in the low-dose and high-dose cohorts.