Intrapulmonary Penetration of Posaconazole in Immunosuppressed Mice Receiving Oral Prophylactic Regimens

Ref ID: 18715

Author:

S. Seyedmousavi, DVM, PhD – Scientific Researcher1,2, R. J. M. Brüggemann, PhD – Clinical Pharmacist 1,2, W. J. G. Melchers, PhD – Associate Professor 1,2, P. E. Verweij, MD, PhD – Professor 1,2, J. W. Mouton, MD, PhD – Professor 1,2;

Author address:

1Radboud Univ. Nijmegen Med. Ctr., Nijmegen, Netherlands, 2Nijmegen Inst. for Infection, Inflammation and Immunity, Nijmegen, Netherlands.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Inhalation of Aspergillus fumigatus conidia is the most common route of infection in Aspergillus diseases. Adequate drug penetration to the infection site is crucial for antifungal therapeutic optimization. To that purpose, we determined posaconazole (POS) concentrations in pulmonary epithelial lining fluid (ELF) and compared to the blood levels. Methods: A total of 96 outbred CD-1 immunosuppressed mice were used. Animals received 0, 4, 8, 16 or 32 mg/kg of body weight POS once daily at days -2, -1, and 0 by oral gavage. On day zero mice were infected with the A.fumigatus isolate (MIC POS 0.5 mg/l) through instillation of conidial suspension in the nares. Blood and BAL samples were drawn at 8 predefined time points postchallenge (0, 0.5, 1, 2, 4, 8, 12 and 24h, 3 mice per each time-point). POS concentration in blood and BAL were assayed by a validated HPLC method. he concentration of POS in ELF was calculated by determination of blood and BAL urea concentration utilizing QuantiChromTM Urea Assay Kit (DIUR-500)( BioAssay Systems). Results: The maximum concentrations (Cmax) in plasma were 5.51, 8.70, 10.92 and 15.04 mg/L and in ELF 1.58, 2.83, 3.62 and 5.32 mg/L for dosages of 4, 8, 16 and 32 mg/kg, respectively. A significant correlation between POS concentration in blood and ELF was noted by linear regression analysis (r2 =0.75, P< 0.0001). Area under the concentration-time curve from 0 to 24 h (AUC0-24) for plasma were 73.61, 151.1, 201.3 and 293.3 (hr*mg/L). The AUC correlated significantly with the dose in a linear fashion from 4-32 mg/kg (r2 =0.94). Penetration of POS into ELF was calculated as ELF: plasma AUC0-24 ratio between 13.88 and 31.33%. Conclusion: POS doses yields ELF concentrations above MIC of utilized fungal isolate. This investigation seems promising to address the target site penetration of POS and also evaluate the dose and exposure-response relationships in preclinical pharmacokinetics and pharmacodynamics studies of IA.

Abstract Number: A-1933

Conference Poster: y

Conference Year: 2012

Link to conference website: NULL

New link: NULL

Conference abstracts, posters & presentations

Showing 10 posts of 17325 posts found.

  • Title

    Author

    Year

    Number

    Poster