title: A semi-mechanistic absorption model to evaluate drug-drug interaction with dabigatran: application with clarithromycin.
abstract: OBJECTIVE
  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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratoire de Pharmacologie Toxicologie, University Hospital of Saint-Etienne, Saint-Etienne, France. xavier.delavenne@chu-st-etienne.fr
authors.forename: Xavier
authors.initials: X
authors.lastname: Delavenne
authors.forename: Edouard
authors.initials: E
authors.lastname: Ollier
authors.forename: Thierry
authors.initials: T
authors.lastname: Basset
authors.forename: Laurent
authors.initials: L
authors.lastname: Bertoletti
authors.forename: Sandrine
authors.initials: S
authors.lastname: Accassat
authors.forename: Arnauld
authors.initials: A
authors.lastname: Garcin
authors.forename: Silvy
authors.initials: S
authors.lastname: Laporte
authors.forename: Paul
authors.initials: P
authors.lastname: Zufferey
authors.forename: Patrick
authors.initials: P
authors.lastname: Mismetti
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000991:Antithrombins / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D001780:Blood Coagulation Tests; D017291:Clarithromycin / Q000494:pharmacology*; D018592:Cross-Over Studies; D000069604:Dabigatran; D004347:Drug Interactions; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011725:Pyridines / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000991:Antithrombins; D001562:Benzimidazoles; D011725:Pyridines; D010450:Endopeptidases; C020097:ecarin; D017291:Clarithromycin; D000069604:Dabigatran