Pharmacokinetics and pharmacodynamics of a novel triazole, isavuconazole: mathematical modeling, importance of tissue concentrations, and impact of immune status on antifungal effect

Abstract

Isavuconazole is a triazole with broad-spectrum activity against medically important fungal pathogens. We investigated the pharmacokinetics and pharmacodynamics of isavuconazole in a murine model of disseminated candidiasis. We determined the pharmacokinetics in both plasma and kidney. The relationship between tissue concentrations and the resultant antifungal effect was described using a mathematical model. The pharmacodynamic parameter that optimally links drug exposure with the antifungal effect was determined using dose fractionation studies. The impact of the immune status of mice receiving isavuconazole was determined in persistently and temporarily neutropenic animals. The pharmacokinetics of 1.6 to 28 mg isavuconazole/kg of body weight were linear. Exposure-response relationships demonstrated near-maximal effect following the administration of >15 mg/kg. The mathematical model showed that exposures in the kidney were 5.77 times higher than those in plasma, and there was persistence of the drug at this site despite concentrations in plasma falling to undetectable levels. The in vitro and in vivo postantifungal effects were 2 to 5 and 8.41 h, respectively. The area under the concentration-time curve (AUC)/MIC ratio was the parameter that optimally linked drug exposure with the observed antifungal effect. The total drug AUC/MIC ratios associated with a 90% probability of survival in temporarily and persistently neutropenic mice were 270 and 670, respectively. Once corrected for protein binding, these values are similar to the magnitude of drug exposure associated with a high probability of a successful therapeutic outcome for other triazoles. This study provides the experimental foundation for the use of isavuconazole in patients with disseminated candidiasis.

FIG. 1.

(A) Single-dose pharmacokinetics of isavuconazole in plasma following administration of the prodrug. (B) Pharmacokinetics of isavuconazole in the kidney following five doses of the prodrug. The data are means ± standard deviations for three mice at each sampling time.

FIG. 2.

Exposure-response relationship following the administration of isavuconazole. The data are means ± standard deviations of three or four mice. The solid line is the fit of the inhibitory sigmoid E_max model to the data.

FIG. 3.

(A) Observed-predicted plots after the Bayesian step for the concentrations of isavuconazole in plasma. (B) Concentrations of isavuconazole in the kidney. (C) Fungal density in the kidney.

FIG. 4.

Simulations of the time course of isavuconazole in plasma (A) and kidney (B) and the growth of Candida in the kidney (C) in mice receiving 28 mg/kg isavuconazole as the active drug. The open squares represent raw data from individual mice (A and B) or the means of three or four mice (C) receiving 28 mg/kg isavuconazole as the active drug. The closed squares in panel C represent the fungal burden in vehicle-treated controls. The solid line represents the fit of the mathematical model to the pharmacokinetic and pharmacodynamic data.

FIG. 5.

Regressions from the dose fractionation experiments. (A) Total drug peak concentration/MIC versus effect. (B) Total drug AUC/MIC versus effect. (C) Fraction of the dosing interval in which total drug concentrations are more than the MIC. The data are means ± standard deviations for six mice. The solid line is the fit of the inhibitory sigmoid E_max model to the data.

FIG. 6.

Probability of survival for persistently versus temporarily neutropenic mice as a function of the total drug AUC/MIC at steady state.