Two Phase 1, Open-Label, Mass Balance Studies to Determine the Pharmacokinetics of (14) C-Labeled Isavuconazonium Sulfate in Healthy Male Volunteers.
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Townsend R, Kato K, Hale C, Kowalski D, Lademacher C, Yamazaki T, Akhtar S, Desai A
Two Phase 1, Open-Label, Mass Balance Studies to Determine the Pharmacokinetics of (14) C-Labeled Isavuconazonium Sulfate in Healthy Male Volunteers.
Clin Pharmacol Drug Dev. 2018 Feb;7(2):207-216. doi: 10.1002/cpdd.376. Epub 2017 Jul 27.
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- 28750160 [ View in PubMed]
- Abstract
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.
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