Effects of Age and Sex on the Pharmacokinetics of Isavuconazole

Background: This phase 1, open-label, parallel group, single dose study evaluated the pharmacokinetics (PK) of isavuconazole after a single oral dose of isavuconazonium sulfate in healthy non-elderly (18 – 45 y) and elderly (≥65 y) male and female subjects.

Methods: Overall, 48 subjects were enrolled in the study (12 male, 12 female non-elderly and 12 male, 12 female elderly subjects). All subjects received a single oral dose of the prodrug isavuconazonium sulfate equivalent to 200 mg isavuconazole (fasting conditions). PK samples for isavuconazole plasma concentrations were collected predose to 336 hours postdose. Data was analyzed using population PK analysis.

Results: The initial model resulted in a 2-compartment model, with unique clearance (CL) values for each group (Table 1). Due to the similarity in CL values between non-elderly males and elderly males, male subjects were grouped together, while elderly and non-elderly female subjects remained as separate distinct groups. Further modeling resulted in a 2-compartment model with Weibull absorption function. No covariates were significant on exposure. CL values from the best model are presented in Table 2. Total area under the concentration curve (AUC) were calculated using the standard formula (AUC=F1*Dose/CL) based on the individual parameter estimates. Elderly females had the highest exposure of all groups studied (total AUC 138%, 90% CI: 118%, 161%) versus males and (total AUC 147%, 90 % CI: 123%, 176%) versus non-elderly females. Non-elderly females had similar exposure to males (total AUC, 94%, 90% CI: 80%, 109%).

Conclusion: Population PK analysis showed that elderly female subjects had lower CL values for isavuconazole compared with all other subjects. However, the PK difference is not clinically relevant. Therefore no dose adjustments are recommended based on age or gender.

Table 1: CL values for different groups based on age and sex

Parameter	Non-Elderly Male Mean (SD)	Elderly Male Mean (SD)	Non-Elderly Female Mean (SD)	Elderly Female Mean (SD)
CL (L/hr)	1.94 (0.52)	2.04 (0.52)	2.13 (0.39)	1.44 (0.43)

Table 2: CL values from the best model

Parameter	Male Mean (SD)	Non Elderly Female Mean (SD)	Elderly Female Mean (SD)
CL (L/hr)	2.07 (0.52)	2.17 (0.38)	1.51 (0.44)