title: Impact of Mucositis on Absorption and Systemic Drug Exposure of Isavuconazole.
abstract: Isavuconazonium sulfate is the water-soluble prodrug of isavuconazole. Population analyses have demonstrated relatively predictable pharmacokinetic (PK) behavior in diverse patient populations. We evaluated the impact of mucositis on the oral isavuconazole exposure using population PK modeling. This study included patients treated in two phase 3 trials of isavuconazole, SECURE for treatment of invasive aspergillosis (IA) and other filamentous fungi and VITAL for patients with mucormycosis, invasive fungal disease (IFD) caused by other rare fungi, or IA and renal impairment. Mucositis was reported by site investigators and its impact on oral bioavailability was assessed. Use of the oral formulation was at the discretion of the investigator. Patients with plasma samples collected during the use of isavuconazonium sulfate were included in the construction of population PK model. Of 250 patients included, 56 patients had mucositis at therapy onset or as an adverse event during oral isavuconazole therapy. Levels of oral bioavailability were comparable, at 98.3% and 99.8%, respectively. The average drug exposures (average area under the curve [AUCave]) calculated from either the mean or median parameter estimates were not different between patients with and without mucositis. Mortality and overall clinical responses were similar between patients receiving oral therapy with and without mucositis. We found that isavuconazole exposures and clinical outcomes in this subset of patients with mucositis who were able to take oral isavuconazonium sulfate were comparable to those in patients without mucositis, despite the difference in oral bioavailability. Therefore, mucositis may not preclude use of the oral formulation of isavuconazonium sulfate.
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.|Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA.
authors.forename: Laura L
authors.identifier: 0000-0002-4493-4652
authors.initials: LL
authors.lastname: Kovanda
authors.affiliation: Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Marty
authors.affiliation: Universitaire Ziekenhuizen, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Maertens
authors.affiliation: Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA.
authors.forename: Amit V
authors.initials: AV
authors.lastname: Desai
authors.affiliation: Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lademacher
authors.affiliation: Basilea Pharmaceutica International Ltd., Basel, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Engelhardt
authors.affiliation: Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA.
authors.forename: Qiaoyang
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom william.hope@liverpool.ac.uk.
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy* / Q000401:mortality; D001682:Biological Availability; D005260:Female; D006801:Humans; D000072742:Invasive Fungal Infections / Q000188:drug therapy / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D009091:Mucormycosis / Q000188:drug therapy* / Q000401:mortality; D052016:Mucositis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009570:Nitriles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011725:Pyridines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome; D014230:Triazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole
keywords: antifungal agents; aspergillosis; invasive fungal disease; mucormycosis; mucositis; population pharmacokinetics; triazole