No Dose Adjustment for Isavuconazole Based on Age or Sex

Abstract

This phase 1, open-label, single-dose, parallel-group study evaluated the pharmacokinetics (PK) of isavuconazole after a single oral dose of the prodrug isavuconazonium sulfate in healthy nonelderly (age, 18 to 45 years) and elderly (age, ≥65 years) males and females. Overall, 48 subjects were enrolled in the study (n = 12 each in groups of nonelderly males and females and elderly males and females). All subjects received a single oral dose of 372 mg of isavuconazonium sulfate (equivalent to 200 mg isavuconazole). PK samples were collected for analysis of isavuconazole plasma concentrations from the predose time point up to 336 h postdose. Data were analyzed using population pharmacokinetic (PPK) analysis. The resulting PPK model included two compartments with Weibull absorption function as well as interindividual variability with respect to clearance, intercompartment clearance, volumes of central and peripheral compartments, and two Weibull absorption parameters, RA and KAMAX. The PPK analysis showed that elderly females had the highest exposure versus males (ratio of total area under the time-concentration curve [AUC], 138; 90% confidence interval [CI], 118 to 161) and versus nonelderly females (ratio of AUC, 147; 90% CI, 123 to 176). Higher exposures in elderly females were not associated with significant toxicity or treatment-emergent adverse events, as measured in this study. No dose adjustments appear to be necessary based on either age group or sex even with an increase in exposure for elderly females. (This study has been registered at ClinicalTrials.gov under registration no. NCT01657890.).

Keywords: age; isavuconazole; pharmacokinetics; sex.

FIG 1

Means ± standard deviations of plasma concentrations of isavuconazole by age group and sex in the pharmacokinetic analysis set. The inset shows an expanded 0-to-48-h interval.

FIG 2

Isavuconazole clearance values for the different groups based on age and sex in subjects from the pharmacokinetic analysis set. Boxes represent medians and 25th and 75th percentiles, whiskers represent 1.5× the interquartile range, solid gray circles represent means, and open circles represent outliers. CL, clearance.

FIG 3

Isavuconazole clearance values from the two-compartment model in the pharmacokinetic analysis set. Boxes represent medians and 25th and 75th percentiles, whiskers represent 1.5× the interquartile range, solid gray circles represent means, and open circles represent outliers. CL, clearance.