Mechanism-based pharmacokinetic-pharmacodynamic models of in vitro fungistatic and fungicidal effects against Candida albicans

Antimicrobial Agents and Chemotherapy
Nicolas VenisseWilliam Couet

Abstract

Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models describing the fungistatic activity of fluconazole and the fungicidal activity of caspofungin were developed using dynamic in vitro models. Antifungal-drug pharmacokinetics was simulated in vitro, assuming a one-compartment model with an elimination half-life of 3 h and using a wide (1 to 10,000) range of initial concentrations. The number of CFUs over time was determined for up to 31 h and used for PK-PD modeling. A model incorporating first-order natural growth and natural death, plus a maximum number of viable Candida cells, was used to characterize Candida growth in the absence of a drug. Fluconazole was considered to inhibit Candida growth and caspofungin to stimulate Candida death according to an Emax pharmacodynamic model. The data were analyzed with Nonmem, using a population approach. A good fit of the data was obtained with satisfactory estimates of PK-PD parameters, especially with drug concentrations producing 50% of the maximal effect: 50% inhibitory concentrations for fluconazole growth inhibition and 50% effective concentrations for caspofungin death stimulation. In conclusion, mechanistic PK-PD models were successfully developed to describe, respecti...Continue Reading

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