title: 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.).
authors.affiliation: Department I of Internal Medicine, ZKS Köln (BMBF 01KN1106), Center for Integrated Oncology CIO KölnBonn, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
authors.affiliation: Onkologikum Frankfurt am Museumsufer, Frankfurt, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Böhme
authors.affiliation: Basilea Pharmaceutica International Ltd., Basel, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Schmitt-Hoffmann
authors.affiliation: Department of Hematology, Oncology and Pneumology, Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany andrew.ullmann@uni-wuerzburg.de.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ullmann
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D015470:Leukemia, Myeloid, Acute / Q000150:complications*; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy / Q000517:prevention & control*; D009503:Neutropenia / Q000150:complications*; D009570:Nitriles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D061214:Patient Safety; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole