Two Phase 1, Open‐Label, Mass Balance Studies to Determine the Pharmacokinetics of ¹⁴C‐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‐14C]isavuconazonium sulfate corresponding to 200 mg isavuconazole. Six subjects in study 2 (BAL8728 mass balance) received a single intravenous dose of [pyridinylmethyl‐14C]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.

Tissue Distribution and Elimination of Isavuconazole following Single and Repeat Oral-Dose Administration of Isavuconazonium Sulfate to Rats

“…For the studies with radiolabeled isavuconazonium sulfate, we could not determine the contribution of the by-products of isavuconazole metabolism to the radioactivity in any tissues. Indeed, given that about half of the active isavuconazole moiety in humans is excreted as metabolites in urine ( 31 ), that was likely to be a substantial contributor to the radioactivity detected in kidney and urinary tract tissues. Furthermore, these studies were conducted in healthy animals, and so it is not clear whether the extent of tissue penetration might be substantially affected by inflammation associated with infection.…”

The nested enzyme-within-enterocyte (NEWE) turnover model for predicting dynamic drug and disease effects on the gut wall

“…Predictions of the impact of mucositis were carried out for isavuconazole, broad spectrum antifungal agent, BCS class I (highly soluble and permeable). The drug displays a low intravenous clearance and is mainly metabolised by CYP3A4, predicting an FG of approximately 0.93 (Townsend et al, 2018, Falci and Pasqualotto, 2013, Schmitt-Hoffmann et al, 2006. Kovanda, and co-workers (Kovanda et al, 2017), reported a statistically insignificant reduction in oral AUC (ratio of 0.92) and oral bioavailability (ratio of 0.88) ( Figure 7A and 7B).…”

“…(Yang et al, 2007, Gertz et al, 2010. For isovuconazole, CLuint was back-calculated from intravenous clearance assuming CYP3A4 metabolism only (Townsend et al, 2018). FG values in gut disease were then predicted using the Qgut model (See Supplementary Material S4 for more details) and compared to observed pharmacokinetic parameters, AUC and Cmax (maximum concentration).…”

Antifungal Drugs TDM: Trends and Update

“…266,270 Mucositis may not rule out oral ISZ use. 268,278 Unlike those of VRZ and PSZ, the IV formulation of ISZ contains no cyclodextrin, as it is water-soluble, and the associated risk of nephrotoxicity is, therefore, very low. 279 ISZ is contraindicated in patients with familial short-QT syndrome.…”