Background: Isavuconazonium sulfate, the water-soluble prodrug of the broad-spectrum, triazole antifungal, isavuconazole (ISAV) was developed for the treatment of invasive fungal disease (IFD). The objective of this analysis was to determine if ISAV pharmacokinetics is different in obese vs. non-obese patients with fungal infections and if a dose adjustment is necessary in obese patients.
Methods: Patients from 3 clinical studies (SECURE, ACTIVE and VITAL) were combined for this analysis. 74 patients (~ 25 from each study) were classified as obese (BMI > 30 kg/m2) as described in the protocols for the 3 clinical studies. 144 non-obese patients (~2:1 ratio) were randomly selected from the 3 clinical studies (~48 from each study). Concentration-time data were analyzed using population pharmacokinetic model developed in NONMEM. Obesity was investigated as the covariate of interest.
Results: 2-compartment models with first order absorption and linear elimination fit the data adequately. Obesity was only significant on peripheral volume of distribution and no other parameter of interest. Area under the curve (AUC) was calculated using the standard formula (F1*DOSE/Clearance), where clearance was obtained from the empirical Bayes estimates for each individual patients. No apparent difference in AUC was observed between obese and non-obese patients (Figure 1). The geometric mean AUC in obese patients was 68 mg*hr/L as compared to 73 mg*hr/L in non-obese patients (p=0.17).
Conclusion: Due to similarity in exposures between obese and non-obese patients across 3 clinical studies, no isavuconazole dose adjustment is necessary for obese patients.
Figure1: Box plot of AUC values vs. Obesity
D. R. Andes, University of Wisconsin: Employee and Shareholder , Salary
C. Lademacher, Astellas: Employee , Salary
R. Townsend, Astellas: Employee , Salary
M. Engelhardt, Basilea: Employee , Salary
P. Bonate, Astellas Pharma Global Development, Inc.: Employee , Salary
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