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.