Isavuconazonium sulfate is the water-soluble prodrug of the broad-spectrum, triazole antifungal, isavuconazole (ISC), developed for the treatment of invasive fungal disease (IFD). A population PK (PPK) analysis was conducted in patients who received isavuconazonium sulfate as part of the phase 3 trial (VITAL) for the treatment of IFD, including invasive mucormycosis (IM) and invasive aspergillosis (IA).
Data for modelling were from the VITAL (NCT00634049) trial, which evaluated efficacy and safety of ISC in the treatment of IA in patients with renal impairment, and in patients with IFD caused by emerging moulds, yeasts, and dimorphic fungi. ISC dosing regimen was 200mg (IV or oral) TID for 2 days, then 200mg QD (IV or oral). Study design and eligibility criteria are available at clinicaltrials.gov. A non-parametric PPK model was developed using Pmetrics software (v1.3.2, U of Southern CA). Covariates examined were body mass index, weight, and race on clearance (Cl). After developing the PPK model considering covariates, the subset of patients with IM was evaluated separately and were compared to that of the overall dataset and also to the subset of IA patients from the VITAL trial and IA patients from SECURE trial (ICAAC 2014 A-697).
451 concentrations from 136 patients were available. A 2-compartment model with first order absorption fit the data well. None of the covariates were found to significantly impact Cl. PK parameters from the subset of 35 patients with IM were similar to the overall VITAL patients and the subset of IA patients from the VITAL study as seen in Table 1.
Table 1: ISC Population PK parameters from VITAL trial
|PK Variables (mean)||Overall
|Cl (L/h)||2.6 (±1.6)||2.9 (±2.0)||2.4 (±1.9)|
|V (L)||352 (±124)||352 (±124)||372 (±159)|
|%CV on AUC||60.3||76.1||70.4|
ISC Cl does not differ across various P3 populations including IM and IA patients from the VITAL trial and similar to the reported Cl values from patients with IA in the P3 SECURE analyses. The inter-subject variability in AUCs between the 2 studies was also similar.
- ICAAC 55th (2015)