Translation of a physiologically‐based pharmacokinetic model for dabigatran etexilate to the design of a safety and efficacy study in post‐partum women

Aims To translate a PBPK model developed for the direct oral anticoagulant, dabigatran etexilate, the prodrug of dabigatran, based on data obtained from healthy men to healthy non‐pregnant, pregnant and post‐partum women. To evaluate safety and efficacy of dabigatran etexilate in post‐partum women using simulations and design a future clinical study to support model verification. Methods An integrated PBPK/PD model in healthy non‐pregnant, pregnant and post‐partum women was translated from the PBPK model in healthy men by capturing physiological changes. The model was also linked to established exposure‐response relationships for coagulation indices and plasma‐breast milk transfer using data from a pilot study. Finally, the model was used for simulation and the design of a prospective clinical study. Results The model predicted comparable plasma concentration profiles between healthy men and healthy, pregnant and post‐partum women, by capturing their physiological differences. The model also captured plasma concentration and activated partial thromboplastin time (a coagulation index) data from a pilot study in post‐partum women available in the literature. A sample size of 20 and 50–60 were determined to be appropriate for safety and efficacy arms respectively, of a clinical trial for model verification. Conclusion An integrated PBPK/PD model for dabigatran etexilate in post‐partum women has been developed successfully. The model was used to design a future clinical trial examining safety and efficacy of dabigatran in postpartum women at risk of thromboembolism.