Population Pharmacokinetics, Exposure-Safety, and Probability of Target Attainment Analyses for Isavuconazole in Japanese Patients With Deep-Seated Mycoses.

Abstract

Isavuconazonium sulfate is the water-soluble prodrug of the novel, broad-spectrum, triazole antifungal agent isavuconazole. Its pharmacokinetics (PK) and exposure-response relationship have been well investigated, but not in a Japanese patient population. The objectives of this analysis were to (1) develop a population PK model for Japanese patients with deep-seated mycoses and healthy subjects, and to identify significant covariates; (2) determine the probability of PK-pharmacodynamic (PK-PD)target attainment in Japanese patients by a clinical dosing regimen; and (3) evaluate the exposure-safety relationship of isavuconazole in Japanese patients. Data from 2 phase 1 studies and 1 phase 3 study in Japanese patients were pooled to develop the population PK model using NONMEM. The PK of isavuconazole in Japanese patients was best described as a 2-compartment model with a Weibull absorption function and first-order elimination. The identified covariates on clearance were creatinine clearance and lean body mass. The probability of target attainment showed that >90% of simulated Japanese patients would achieve the PK-PD target, an exposure index corresponding to 50% survival of nonneutropenic infected mice, with minimal inhibitory concentration values of ≤1mg/L according to Clinical and Laboratory Standards Institute methodology and of ≤2mg/L according to European Committee on Antimicrobial Susceptibility Testing methodology by the clinical dosing regimen. No apparent relationships were found for any of the exposure parameters of isavuconazole with any assessed safety end points in Japanese patients. Taken together, the clinical dosing regimen is appropriate for the treatment of Japanese patients with deep-seated mycoses.