Population Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

Isavuconazole (ISA) is a triazole antifungal with activity against yeasts and molds. We established a population pharmacokinetic (pop PK) model of intravenous (i.v.) ISA to identify covariates that affect pharmacokinetics, using plasma samples from solid-organ transplant (SOT) recipients receiving peritransplant prophylaxis. Samples (n = 471) from 79 SOT recipients were utilized for pop PK analysis using nonlinear mixed-effect modeling NONMEM software. ISA (i.v.) PK parameters were best described by a two-compartment model. Significant covariates were sex on clearance (similar to 53% higher in women than men) and body mass index on peripheral volume of distribution. Incorporating drug exposure into Monte Carlo simulations, we demonstrated that standard ISA dosing is likely to attain the PK-pharmacodynamic (PD) target (area under the concentration curve/MIC ratio [AUC/MIC]) for treatment effectiveness against almost all infections caused by Aspergillus fumigatus isolates exhibiting MICs of <0.5 mu g/ml (modal MIC). In contrast, standard dosing is predicted to attain PK-PD targets against <20% of infections caused by Candida albicans and Candida glabrata isolates exhibiting MICs of >0.016 and >0.5 mu g/ml, respectively (modal MICs). These data are consistent with our SOT program's experience with ISA breakthrough infections, where 3 of 4 were caused by C. glabrata for which probabilities of PK-PD target attainment (PTA) were only 70% and 0% for isolates with MICs of 0.25 mu g/ml and 1 mu g/ml. Our findings provide important new insights into how ISA use might be optimized following SOT.