An in Vitro Pharmacokinetic/Pharmacodynamic Model Predicts in vivo Outcome of Voriconazole Treatment against Aspergillus fumigatus Isolates with Reduced Azole Susceptibility

Ref ID: 18665

Author:

M. Siopi, MS – PhD student1, E. Mavridou, PhD – PhD student 2, A. Elefanti, PhD – PhD student 1, P. E. Verweij, MD – Professor 2, J. W. Mouton, MD – Professor 2, J. Meletiadis, PhD – Lecturer 1;

Author address:

1Attikon Univ. Gen. Hosp., Athens, Greece, 2Radboud Univ. Med. Ctr., Nijmegen, Netherlands.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Voriconazole (VCZ) is the first-line treatment of invasive aspergillosis. The alarming increase in the frequency of azole-resistant (AR) Aspergillus fumigatus (AFM) requires reevaluation. We studied the efficacy of VCZ using a new pharmacokinetic/pharmacodynamic in vitro (PK/PD) model with the results obtained in animal models. Methods: Four clinical AFM isolates, one wild-type strain with MIC 0.25 mg/L and three strains with defined CYP51A mutations with MICs 0.125, 0.25 and 2 mg/L, previously tested in animal models, were included (Mavridou et al AAC 2010). VCZ dosages of 10, 40 and 80 mg/kg/od were simulated in a newly developed two-compartment in vitro PK/PD model (IVPM) based on dialysis with Cmax 1.60, 11.09 and 36.49 mg/L, respectively, and average half-life of 6h. The AUC0-24 and the area under the galactomannan index-time curve AUCGI after 3 days were determined for each dose and isolate. The in vitro relationship of % fungal growth-fAUC/MIC was correlated with the in vivo mortality-fAUC/MIC after 15 days of treatment. Results: Fungal growth was progressively inhibited at higher VCZ concentrations, while drug efficacy was reduced as the MIC was increased. The in vitro PK parameters and % of antifungal efficacy were similar with those observed in animal models (p=0.4). The in vitro % fungal growth-AUC/MIC followed a sigmoid curve similar to that of the animal model (R2=0.91). The fAUC0-24/MIC corresponding to 50% maximal activity was 11.53 (range 8-16) in the in vitro model close to the in vivo AUC0-24/MIC of 10.5. Conclusions: The in vitro and in vivo efficacy of VCZ was dependent both on drug exposure and MIC of the isolate. The results of the new IVPM were comparable with those obtained from the animal model providing thus a useful and reliable tool alternative to animal models and substantiating PK/PD relationships of antifungals.

Abstract Number: A-1938

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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