Background: ISA, the active moiety of the water soluble prodrug isavuconazonium sulfate, is a novel triazole antifungal agent for treatment of invasive fungal infections. The objective of this analysis was to develop a population pharmacokinetic (PPK) model, to identify covariates that affect ISA pharmacokinetics (PK) and to determine the probability of target attainment (PTA) over a range of Minimum Inhibitory Concentration (MIC) values. Methods: Data from 9 Phase 1 (P1) studies and 1 Phase 3 (P3) study were pooled from subjects administered single and multiple, oral and intravenous (IV) doses of ISA ranging from 40 to 400 mg. PPK models were developed with NONMEM version 7.2 (GloboMax LLC, Hanover, MD). Covariates examined included various continuous covariates (age, weight, height, lean body mass, body mass index (BMI), creatinine clearance, liver function tests), and categorical covariates (race, sex, differences between patients and healthy subjects, CYP3A conmeds). Stepwise covariate modeling (SCM) was performed in Pearl-speaks-NONMEM (PSN) by using the forward selection (α = 0.01) and backward elimination (α = 0.001) method. Area under the curve (AUC) to steady state was calculated for 5000 simulated patients based on parameter estimates. PTA using the total AUC/MIC ratio estimated from in vivo pharmacodynamic studies of invasive aspergillosis over a range of MIC values was calculated using Monte Carlo simulations. Results: 6363 concentration records (5828 from P1 studies/535 from P3 study) from 189 subjects and 232 patients were used. A 2-compartment model with Weilbull absorption function and first order elimination process adequately described plasma ISA concentrations. The population mean estimate for clearance (CL) was 2.39L/hr and mean AUC0-24 was ~100 µg·hr/L. Asian population had ~ 40% decreased total CL compared to Caucasian population. Peripheral volume of distribution increased with BMI. PTA was calculated over a range of MIC values. Conclusions: A 2-compartment model adequately described the data. No PK differences were noted between patients and healthy volunteers. PTA confirmed the appropriateness of the 200 mg TID loading regimen D1/2, followed by the 200 mg daily dose used in P3 clinical trials.
Full conference title:
- ICAAC 54th (2014)