Posaconazole PK/PD in preclinical studies Sample Clauses

Posaconazole PK/PD in preclinical studies. Prophylaxis Posaconazole given as prophylactic therapy against pulmonary aspergillosis showed a dose-(and concentration)-dependent response in a neutropenic rabbit model and a neutropenic murine model [6, 11]. In the rabbit model, posaconazole was administered orally with 3 dosing levels of 2, 6, and 20 mg/kg/day 4 h before endotracheal inoculation with A. fumigatus. Rabbits receiving prophylactic posaconazole at all dosages showed a significant reduction in infarct scores, total lung weights, and organism clearance from lung tissue in comparison to those of untreated controls. A dose-dependent microbiological clearance of A. fumigatus from lung tissue in response to posaconazole was observed [6]. In the murine model, oral posaconazole was administered once daily with 5 dosing levels of 1, 4, 8, 16, and 32 mg/kg and mice were infected through instillation of the inoculum in the nares. A 24h-AUC/MIC ratio (AUC0-24/MIC) of 37.4 (95% confidence interval, 7.1 - 196) was able to achieve half-maximal survival for preventing the pulmonary IFD caused by azole-resistant A. fumigatus for which the MIC against posaconazole was 0.5 mg/L [11]. Table 4 shows the posaconazole exposure-response relationships in various murine mode Treatment In addition to prophylaxis models, many preclinical PK/PD models have been established for the treatment of invasive candidiasis and aspergillosis [5-10]. The posaconazole exposure-response relationship was described using an inhibitory sigmoid Emax model based on an in vitro human alveolus model consisting of a bilayer of human alveolar epithelial and endothelial cells [8, 80]. EC50 with an AUC/ MIC ratio of 2.2 and 11.6 was observed in endothelial and alveolar compartments of an in vitro model infected with A. fumigatus, respectively, and an AUC/MIC ratio of 100 was able to achieve near maximal decrease of galactomannan concentrations in both endothelial and alveolar compartments [8]. The relationship between AUC/MIC and the antifungal response to posaconazole were confirmed in three neutropenic murine models of invasive pulmonary aspergillosis and one non-neutropenic murine model of disseminated aspergillosis, all infected with A. fumigatus strains [7-10]. The AUC0-24/MIC target associated with half-maximal antifungal response differs from model to model, with a ratio of the AUC/MIC of 321 when using mice mortality as endpoints [7] versus an AUC/MIC ratio of 167 when using the decline in serum galactomannan concentrations as end poi...
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