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Clinical Trial
. 2025 Feb;13(1):e70064.
doi: 10.1002/prp2.70064.

Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Inhaled Voriconazole in Healthy Volunteers and Subjects With Stable Asthma

Giovanni Caponetti  1 , Federica Sala  1 , Antonio Cervetti  1 , Daniele Colombo  1 , Elena Tiberio  1 , Dave Singh  2   3
Affiliations
Clinical Trial

Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Inhaled Voriconazole in Healthy Volunteers and Subjects With Stable Asthma

Giovanni Caponetti et al. Pharmacol Res Perspect. 2025 Feb.

Abstract

The aim of this study was to evaluate safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of a novel inhaled formulation of voriconazole (ZP-059). In the single ascending dose part, 4 cohorts of 6 healthy subjects received one dose of inhaled voriconazole (5-40 mg). In the multiple ascending dose part, 3 cohorts of 6 subjects with mild asthma received voriconazole 10 mg twice daily [BID], 20 mg BID or 40 mg once daily. In the 2-period crossover part, 16 subjects with mild to moderate asthma each received one dose of inhaled voriconazole 20 mg and one dose of oral voriconazole 200 mg. A bioanalytical method was developed and validated to simultaneously determine concentrations of voriconazole and its metabolite N-oxide voriconazole in serum and sputum. Inhaled voriconazole was well tolerated with no treatment emergent adverse events (TEAEs) leading to treatment discontinuation. The PK profile of inhaled voriconazole showed rapid absorption, apparent greater than proportional increase in exposure with increasing dose, a consistent half-life across dosing, and large clearance and volume of distribution. Following repeat administration limited accumulation was observed. Systemic exposure following inhaled voriconazole was much lower than following oral voriconazole. Serum data confirmed that voriconazole was extensively metabolized also when administered by inhalation. Sputum data following inhaled voriconazole were limited but demonstrated increasing exposure with increasing dose. The current study shows the newly developed dry powder inhaled formulation of voriconazole to be safe and well tolerated, providing a possible improved treatment approach for patients affected by allergic bronchopulmonary aspergillosis. Trial Registration: ClinicalTrials.gov ID: NCT04229303.

Keywords: inhaled; pharmacokinetics; phase I; safety and tolerability; voriconazole.

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Conflict of interest statement

A. Cervetti, D. Colombo, F. Sala, E. Tiberio are current employees of Zambon. G. Caponetti is the inventor of the patents WO2022/1223009 “Method for manufacturing an inhalable powder comprising Voriconazole” and “Inhalable powder comprising Voriconazole in crystalline form” WO2022/123029. D. Singh has received consultancy fees from Aerogen, AstraZeneca, BIAL, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, EpiEndo, Genentech, GlaxoSmithKline, Glenmark, Gossamer Bio, Kinaset Therapeutics, Menarini, Novartis, Orion, Pulmatrix, Sanofi, Teva, Theravance Biopharma, and Verona Pharma.

Figures

FIGURE 1
FIGURE 1
(a) Serum Concentration of Voriconazole Over Time after Single Inhaled Doses (Mean [+SD], Part 1, Day 1). (b) Serum Concentration of Voriconazole Over Time after Single Inhaled Doses (Mean [+SD], Part 2, Day 1). (c) Serum Concentration of Voriconazole Over Time after Multiple Inhaled Doses (Mean [+SD], Part 2, Day 10).
FIGURE 2
FIGURE 2
Serum Concentration of Voriconazole Over Time after a Single Inhaled Dose (20 mg) and a Single Oral Dose (200 mg) (Mean [+SD], Part 3, Day 1).
See this image and copyright information in PMC

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