Isavuconazole Population Pharmacokinetic Analysis Using Nonparametric Estimation in Patients with Invasive Fungal Disease (Results from the VITAL Study)

Abstract

Isavuconazonium sulfate (Cresemba; Astellas Pharma Inc.), a water-soluble prodrug of the triazole antifungal agent isavuconazole, is available for the treatment of invasive aspergillosis (IA) and invasive mucormycosis. A population pharmacokinetic (PPK) model was constructed using nonparametric estimation to compare the pharmacokinetic (PK) behaviors of isavuconazole in patients treated in the phase 3 VITAL open-label clinical trial, which evaluated the efficacy and safety of the drug for treatment of renally impaired IA patients and patients with invasive fungal disease (IFD) caused by emerging molds, yeasts, and dimorphic fungi. Covariates examined were body mass index (BMI), weight, race, impact of estimated glomerular filtration rate (eGFR) on clearance (CL), and impact of weight on volume. PK parameters were compared based on IFD type and other patient characteristics. Simulations were performed to describe the MICs covered by the clinical dosing regimen. Concentrations (n = 458) from 136 patients were used to construct a 2-compartment model (first-order absorption compartment and central compartment). Weight-related covariates affected clearance, but eGFR did not. PK parameters and intersubject variability of CL were similar across different IFD groups and populations. Target attainment analyses demonstrated that the clinical dosing regimen would be sufficient for total drug area under the concentration-time curve (AUC)/MIC targets ranging from 50.5 for Aspergillus spp. (up to the CLSI MIC of 0.5 mg/liter) to 270 and 5,053 for Candida albicans (up to MICs of 0.125 and 0.004 mg/liter, respectively) and 312 for non-albicans Candida spp. (up to a MIC of 0.125 mg/liter). The estimations for Candida spp. were exploratory considering that no patients with Candida infections were included in the current analyses. (The VITAL trial is registered at ClinicalTrials.gov under number NCT00634049.).

FIG 1

Illustration of the structural model, where compartment 1 represents the gut for oral administration and compartment 2 represents the central compartment. CL, clearance; F, bioavailability; Ka, first-order absorption rate constant; Tlag, lag time; V, volume in the central compartment.

FIG 2

Observed versus posterior predicted concentrations (milligrams per liter) from the final model after the Bayesian step (r² = 0.89; slope = 1.05 [95% CI, 1.01 to 1.08]; intercept = −0.0484 [95% CI, −0.179 to 0.0825]). The dotted line is the line of unity where observed concentrations equal predicted concentrations.

FIG 3

Linear regression plots charting the impacts of eGFR on clearance (A), BMI on clearance (B), weight on clearance (C), and weight on volume in the central compartment (D). (A) Linear regression for eGFR (r² and slope were 0.02 and 0 [95% CI, 0 to 0.01], respectively) versus clearance did not find a correlation. (B) There was a significant relationship between BMI and clearance (r² and slope were 0.06 and 0.07 [95% CI, 0.02 to 0.11], respectively). (C) There was a significant relationship between weight and clearance (r² and slope were 0.06 and 0.02 [95% CI, 0.01 to 0.03], respectively). (D) Linear regression showed a significant correlation between weight and volume (r² and slope were 0.06 and 2.36 [95% CI, 0.69 to 4.02], respectively).

FIG 4

Impact of Asian race on clearance. Box plots for the clearance values for Asian patients (n = 23) (median = 1.59 liters/h) and other patients (i.e., non-Asian; includes white, black or African-American, and “other”; n = 113) (median = 1.84 liters/h) did not show a statistically significant difference (P = 0.06; Mann-Whitney U test).

FIG 5

PTA (left y axes) for PD targets estimated in PK-PD animal models for the common fungal pathogens A. fumigatus (A), non-albicans Candida (B), and C. albicans (C). Each graph illustrates the proportion of 5,000 simulated subjects achieving each of the PD targets at each MIC value after administration of the clinical dosing regimen of isavuconazonium sulfate. Isavuconazole CLSI MIC distributions (right y axes) are provided for A. fumigatus (n = 855) (A), C. glabrata (n = 254) and C. tropicalis (n = 130) (B), and C. albicans (n = 844) (C).