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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.

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.

SUBMITTER: Townsend R

PROVIDER: S-EPMC5811773 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Two Phase 1, Open-Label, Mass Balance Studies to Determine the Pharmacokinetics of <sup>14</sup> C-Labeled Isavuconazonium Sulfate in Healthy Male Volunteers.

Townsend Robert R Kato Kota K Hale Christine C Kowalski Donna D Lademacher Christopher C Yamazaki Takao T Akhtar Shahzad S Desai Amit A

Clinical pharmacology in drug development 20170727 2

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-<sup>14</sup> C]isavuconazonium sulfate corresponding to 200 mg isavuconazole. Six subjects in study 2 (BAL8728 mass balance) received a single intravenous dose of [pyridin ...[more]

PMID: 28750160

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Project description:IntroductionAmbroxol is used in the treatment of acute and chronic respiratory conditions characterized by abnormal mucus secretion and impaired mucus transport and is available in a variety of formulations. This study aimed to compare the steady-state (SS) pharmacokinetic characteristics of extended-release (ER) 75-mg retard capsules with two immediate-release (IR) formulations (60-mg effervescent tablets and 30-mg tablets) over a 24-h period.MethodsAn open-label, randomized, three-period, six-sequence crossover study was conducted in healthy volunteers aged 18-45 years who had a normal body mass index. The test (ER 75-mg retard capsule once daily) and reference treatments (half of IR 60-mg effervescent tablet twice daily or 30-mg IR tablet twice daily) were administered on days 1-5 of each treatment period. Meals were standardized and concomitant therapy was prohibited. Blood samples for pharmacokinetic assessment were collected on day 5 (SS) of each treatment period. The co-primary endpoints were exposure (AUCSS 0-24) and maximum plasma level (Cmax SS).ResultsTwenty-four participants received ambroxol (male n = 13, 54.2%; mean ± standard deviation [SD] age 25.0 ± 6.4 years) and 23 completed the study. ER retard capsules provided similar AUCSS 0-24 compared to IR tablets (geometric means ratio [GMR] 110.7%; 90% confidence interval [CI] 99.8%, 122.7%) and effervescent tablets (GMR 106.9%; 90% CI 100.3%, 114.0%). ER retard capsules provided similar Cmax SS compared to IR tablets (GMR 84.7%, 90% CI 77.0%, 93.3%), and lower Cmax SS compared to effervescent tablets (GMR 80.9%, 90% CI 73.9%, 88.6%). Time to Cmax SS (tmax SS) was longer with ER retard capsules (6.0 h) than with IR tablets (2.0 h) or effervescent tablets (1.0 h).ConclusionsER ambroxol 75-mg retard capsules given once daily showed a similar pharmacokinetic profile to IR ambroxol formulations and therefore can be used instead of these in the treatment of respiratory conditions. CLINICALTRIALS.Gov identifierNCT02036775.

Dataset Information

Two Phase 1, Open-Label, Mass Balance Studies to Determine the Pharmacokinetics of ¹⁴ C-Labeled Isavuconazonium Sulfate in Healthy Male Volunteers.

Publications

Two Phase 1, Open-Label, Mass Balance Studies to Determine the Pharmacokinetics of <sup>14</sup> C-Labeled Isavuconazonium Sulfate in Healthy Male Volunteers.

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Dataset Information

Two Phase 1, Open-Label, Mass Balance Studies to Determine the Pharmacokinetics of 14 C-Labeled Isavuconazonium Sulfate in Healthy Male Volunteers.

Publications

Two Phase 1, Open-Label, Mass Balance Studies to Determine the Pharmacokinetics of <sup>14</sup> C-Labeled Isavuconazonium Sulfate in Healthy Male Volunteers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Two Phase 1, Open-Label, Mass Balance Studies to Determine the Pharmacokinetics of ¹⁴ C-Labeled Isavuconazonium Sulfate in Healthy Male Volunteers.