Using an in vitro pharmacokinetics / pharmacodynamics model to simulate and assess the pharmacodynamic characteristics of voriconazole against some Candida albicans isolates in humans

Abstract

Background: Systemic candidiasis can be seen in critically ill patients admitted to intensive care units, with high rates of morbidity and mortality. Candida albicans is the main causative agent of it. Aim: An in vitro pharmacokinetics (PK) / pharmacodynamics (PD) model has been developed in order to assess voriconazole against Candida albicans iso¬lates. Methodology: This model examined the effect of standard dosing regimens of voriconazole (3.0 and 4.0 mg/kg with peak plasma concentrations of 1.5 and 3 mg/L, respectively) on two C. albicans isolates (the sensitive ATCC-90028 and the resistant ATCC-10231). A two-compartment model was used, with a 500-mL beaker filled with RPMI-1640 solution as the external compartment (EC) containing the drug. A peristaltic pump was connected to the beaker so as to circulate the solution into the EC and remove it at the same rate as the drug clearance. Additionally, a dialysis tube was placed in the EC in order to act as an internal compartment (IC), allowing molecules smaller than 20 kD to diffuse freely. The dialysis tubes (IC) were inoculated with C. albicans isolates and incubated, with samples regularly taken for PK and PD studies. PK studies involved sampling from both compartments for drug concentration analysis by using a bioassay, while PD studies monitored fungal growth by assessing the relative optical density. Results: The two simulated doses of 3.0 and 4.0 mg/kg of voriconazole effectively inhibited the growth of the two C. albicans isolates in a dose-dependent manner. The exposure-effect analysis showed over 99% efficacy with 4.0 mg/kg of the drug. Conclusion: Overall, the in vitro PK/PD system accurately demonstrated a significant growth inhibition with both stand¬ard doses (3.0 and 4.0 mg/kg) of voriconazole, in a dose-dependent manner.