AIMThe 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.
METHODSTen 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.
RESULTSThe best PK model was based on an inverse Gaussian 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.
CONCLUSIONThe model proposed effectively describes the complex PK of dabigatran and takes into account drug-drug interactions with P-gp activity modulators, such as clarithromycin.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Dabigatran etexilate has a bioavailability of 6.5% due to a complex absorption process.• Dabigatran etexilate is a substrate for P-gp and its reflux can be modulated by other drugs.• P-gp inhibitors increase the AUC of dabigatran from about 50% to over 200%.
WHAT THIS STUDY ADDS• The pharmacokinetics and pharmacodynamics of dabigatran were described by a two compartment model with an absorption following an inverse Gaussian law, associated with a linear effect model. • We showed that this phenomenon is explained solely by an increase in bioavailability from 6.5 to 10%. • Exposure to dabigatran is increased by 50% in the presence of clarithromycin and is characterized by substantial variability.
This study allowed identification of three different profiles of ABC carrier-mediated transport: predominantly P-gp-dependent transport (dabigatran), preferential BCRP-dependent transport (apixaban) and approximately equivalent P-gp and BCRP-mediated transport (edoxaban and rivaroxaban).
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