Dose tolerability of chronically inhaled voriconazole solution in rodents

Justin Tolman, Nicole A. Nelson, Stephanie Bosselmann, Jay I. Peters, Jacqueline J. Coalson, Nathan P. Wiederhold, Robert O. Williams

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.

Original languageEnglish
Pages (from-to)25-31
Number of pages7
JournalInternational Journal of Pharmaceutics
Volume379
Issue number1-2
DOIs
StatePublished - Sep 8 2009
Externally publishedYes

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Rodentia
Invasive Pulmonary Aspergillosis
Pulmonary Edema
Fungal Lung Diseases
Inhalation Administration
Pharmaceutical Preparations
Weights and Measures
Lung
Alveolar Macrophages
Edema
Voriconazole
Inflammation
Control Groups
Survival
Mortality
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Tolman, J., Nelson, N. A., Bosselmann, S., Peters, J. I., Coalson, J. J., Wiederhold, N. P., & Williams, R. O. (2009). Dose tolerability of chronically inhaled voriconazole solution in rodents. International Journal of Pharmaceutics, 379(1-2), 25-31. https://doi.org/10.1016/j.ijpharm.2009.06.003

Dose tolerability of chronically inhaled voriconazole solution in rodents. / Tolman, Justin; Nelson, Nicole A.; Bosselmann, Stephanie; Peters, Jay I.; Coalson, Jacqueline J.; Wiederhold, Nathan P.; Williams, Robert O.

In: International Journal of Pharmaceutics, Vol. 379, No. 1-2, 08.09.2009, p. 25-31.

Research output: Contribution to journalArticle

Tolman, J, Nelson, NA, Bosselmann, S, Peters, JI, Coalson, JJ, Wiederhold, NP & Williams, RO 2009, 'Dose tolerability of chronically inhaled voriconazole solution in rodents', International Journal of Pharmaceutics, vol. 379, no. 1-2, pp. 25-31. https://doi.org/10.1016/j.ijpharm.2009.06.003
Tolman, Justin ; Nelson, Nicole A. ; Bosselmann, Stephanie ; Peters, Jay I. ; Coalson, Jacqueline J. ; Wiederhold, Nathan P. ; Williams, Robert O. / Dose tolerability of chronically inhaled voriconazole solution in rodents. In: International Journal of Pharmaceutics. 2009 ; Vol. 379, No. 1-2. pp. 25-31.
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