A semi‐mechanistic absorption model to evaluate drug–drug interaction with dabigatran: application with clarithromycin

Aim The aim of this study was to develop a PK / PD model to assess drug–drug interactions between dabigatran and P ‐gp modulators, using the example of clarithromycin, a strong inhibitor of P ‐gp. Methods Ten healthy male volunteers were randomized to receive in the first treatment period a single 300 mg dose of dabigatran etexilate (DE) and in the second treatment period 500 mg clarithromycin twice daily during 3 days and then 300 mg DE plus 500 mg clarithromycin on the fourth day, or the same treatments in the reverse sequence. Dabigatran plasma concentration and ecarin clotting time ( ECT ) were measured on 11 blood samples. Models were built using a non‐linear mixed effect modelling approach. Results The best PK model was based on an inverse G aussian absorption process with two compartments. The relationship between dabigatran concentration and ECT was implemented as a linear function. No continuous covariate was associated with a significant decrease in the objective function. The concomitant administration of clarithromycin induced a significant change only in DE bioavailability, which increased from 6.5% to 10.1% in the presence of clarithromycin. Clarithromycin increased peak concentration and AUC by 60.2% and 49.1% respectively. Conclusion The model proposed effectively describes the complex PK of dabigatran and takes into account drug–drug interactions with P ‐gp activity modulators, such as clarithromycin.