Daiichi Sankyo Inc. Basking Ridge, New Jersey, United States
Background: The objectives of this analysis were to characterize edoxaban in pediatric patients as follows: (1) develop a population PK model; (2) develop a population PK-PD model to describe the relationship between edoxaban concentration and coagulation markers such as anti-FXa activity (AFXA), APTT, and PT; (4) compare the PK and PD relationships between pediatric and adult patients; (5) explore the relationship between edoxaban exposure and VTE/safety events; and (6) evaluate dosing options in the pediatric patients.
Methods: Concentration and PD data from 208 children from 1 phase I, and 2 phase III studies were used to perform an NLME analysis of the population PK and PKPD. Different compartmental models were evaluated to describe the population PK, while Emax or linear models were used describe the relationship between edoxaban concentration and PD endpoints. The effects of intrinsic/extrinsic factors on edoxaban PK and PK-PD were assessed.
Results: A 2-compartment model adequately described the PK of edoxaban. Significant covariate effects were estimated for renal function, body weight, and formulation on absorption rate. A function based on renal maturation was applied to clearance. The clearance and central volume for a 70 kg patient with an eGFR of 110 mL/min/1.73 m2 were estimated to be 44.2 h/L (CV ~ 34%) and 44.0 L (CV ~ 36%), respectively. Simulations showed exposures across five age groups were comparable to that in adult patients receiving 60 mg once daily dose. The PKPD for AFXA was best fit with an Emax (9.44 IU/mL) model with an EC50 of 819 ng/mL. The PKPD for APTT and PT were best fit with linear models (slopes of 0.0471 and 0.0414 sec*mL/ng).
Conclusion: The models provided a reasonable estimation of the population PK and PD of edoxaban in pediatric patients. Pediatric exposures were consistent with prior adult estimates.
