Higher than predicted posaconazole penetration at the infection site in a murine model of invasive pulmonary aspergillosis

Ref ID: 19436

Author:

S. Seyedmousavi,1 R. J. M. Bruggemann,2 W. J. G. Melchers,3
P. E. Verweij3 and J. W. Mouton3

Author address:

1Radboud University Medical Centre, the Netherlands;
2Department of Pharmacy, Radboud University Nijmegen Medical
centre, the Netherlands and 3Department of Medical
Microbiology, Radboud University Nijmegen Medical Centre,
the Netherlands

Full conference title:

6th Trends in Medical Mycology 2013

Date: 11 October 2014

Abstract:

Objectives Invasive aspergillosis (IA) is an important opportunistic
fungal infection in immunocompromised patients with the overall
mortality ranging between 30 to 88%. Inhalation of Aspergillus fumigatus
conidia is the most common route of infection in IA, there-
fore adequate drug penetration to the infection site is crucial for
optimal efficacy. We aimed to determine posaconazole (POS) concen-
trations in pulmonary epithelial lining fluid (ELF) and compare to the
blood plasma 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 24 h, 3 mice per each time-point). POS
concentration in blood and BAL were assayed by a validated HPLC
method. The concentration of POS in ELF was calculated by determi-
nation of blood and BAL urea concentration utilizing QuantiChromTM
Urea Assay Kit (DIUR-500)(BioAssay Systems).
Results All 96 mice were alive at the time of the sample collection
from 0 to 24 h post challenge and in total 288 samples were
obtained. The maximum total drug concentrations (Cmax) of POS in
plasma were 5.51, 8.70, 10.92 and 15.04 mg/L, while lower
amounts were obtained in ELF (1.58, 2.83, 3.62 and 5.32 mg/L) for
dosages of 4, 8, 16 and 32 mg/kg, respectively. The area under the
concentration-time curve from 0 to 24 h (AUC0-24) for plasma was
correlated significantly with the dose in a linear fashion from 4-
32 mg/kg (r2 = 0.94). The log10 AUC0-24 for plasma were 1.87,
2.18, 2.30 and 2.47(hr.mg/L) and for ELF were 1.18, 1.63, 1.80,
1.61(hr.mg/L), resp. A significant correlation between POS concen-
tration in blood and ELF was noted by linear regression analysis (r2
=0.75, P < 0.0001). Penetration of POS in ELF was calculated with respect to plasma results in a ratio (ELF: plasma AUC0-24 ratio) that was between 0.14 and 0.31. Conclusion Although posaconazole is highly protein bound, ELF concentrations were relatively high. The high intrapulmonary pene- tration of POS may be an advantage for protection against diseases caused by both azole susceptible and azole resistant A.fumigatus with MIC higher than susceptible breakpoints to POS.

Abstract Number: p307

Conference Year: 2013

Link to conference website: NULL

New link: NULL

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