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Two Phase 1, Open‐Label, Mass Balance Studies to Determine the Pharmacokinetics of 14 C‐Labeled Isavuconazonium Sulfate in Healthy Male Volunteers
Author(s) -
Townsend Robert,
Kato Kota,
Hale Christine,
Kowalski Donna,
Lademacher Christopher,
Yamazaki Takao,
Akhtar Shahzad,
Desai Amit
Publication year - 2018
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.376
Subject(s) - pharmacokinetics , urine , medicine , volume of distribution , metabolite , pharmacology , sulfate , chromatography , chemistry , organic chemistry
Isavuconazonium sulfate is the water‐soluble prodrug of the active triazole isavuconazole. Two phase 1 studies were conducted to identify the metabolic profile and mass balance of isavuconazole and BAL8728 (inactive cleavage product). Seven subjects in study 1 (isavuconazole mass balance) received a single oral dose of [cyano‐ 14 C]isavuconazonium sulfate corresponding to 200 mg isavuconazole. Six subjects in study 2 (BAL8728 mass balance) received a single intravenous dose of [pyridinylmethyl‐ 14 C]isavuconazonium sulfate corresponding to 75 mg BAL8728. Pharmacokinetic parameters of radioactivity in whole blood and plasma and of isavuconazole and BAL8728 in plasma were assessed. Radioactivity ratio of blood/plasma, percentage of dose, and cumulative percentage of radioactive dose recovered in urine and feces for isavuconazole and BAL8728 were assessed. Metabolic profiling was carried out by high‐performance liquid chromatography and mass spectrometry. Mean plasma isavuconazole pharmacokinetic parameters included apparent clearance (2.3 ± 0.7 L/h), apparent volume of distribution (301.8 ± 105.7 L), and terminal elimination half‐life (99.9 ± 44.6 hours). In study 1, isavuconazole‐derived radioactivity was recovered approximately equally in urine and feces (46.1% and 45.5%, respectively). In study 2, BAL8728‐derived radioactivity was predominantly recovered in urine (96.0%). Isavuconazole (study 1) and M4 (cleavage metabolite of BAL8728; study 2) were the predominant circulating components of radioactivity in plasma.