Resumo

INTRODUCTION: Systemic fungal infections are an important cause of morbidity and mortality in immunocompromised patients being Candida albicans the pathogen more often associated with these infections. Recently, posaconazole - a new triazole agent - was approved by the FDA to the treatment of invasive fungal infections. The dose recommended for treatment is 400 mg twice a day and was defined by empirical criteria. In the present study, we evaluated the effect of posaconazole against Candida albicans in different dosing regimens, using an in vitro model of infection and analyzing the data by a new approach named PK/PD modeling, where both pharmacokinetics and pharmacodynamics aspects are integrated by mathematic modeling and the parameters derivate can be used to improve regimens in clinical practice. MATERIALS AND METHODS: A one-compartment in vitro model was used to simulate posaconazole plasma levels expected after oral administrations of 100, 200 and 400mg doses (q12h and q24h). Posaconazole was added into the system to reach concentrations equivalent to the peak plasma levels expected after each dose and, by sequential dilution, the drug’s half-live of 24h was simulate in the model. The antifungal effect was evaluated by determining the number of yeasts over time up to 24 h. RESULTS AND DISCUSSION: Posaconazole showed a fungistatic effect against C. albicans and an Emax-model was used to model the dynamic effect as a function of time and fluctuating concentrations using Scientist® v 2.01 software.The mean PK/PD parameters obtained by the modeling were: EC50 (concentration required for half of maximum effect) of 1,10 ± 0,24 μg/mL and kmáx (maximum fungistatic effect) of 1,0 ± 0,62 h-1. The mean values of kmax determined for each dosing regimens showed that the maximum fungistatic effect is achieved when the drug is administered twice compared to once a day, supporting the dose used clinically. By using the parameters determined by this model is possible to predict outcomes with other dosing regimens. CONCLUSION: The PK/PD Emáx model adequately described posaconazole antifungal activity and could be used to compare and optimize drug regimens for this drug. ACKNOWLEADGMENTS: FAPERGS process (# 111656-1).