title: Oral bioavailability of dabigatran etexilate (Pradaxa(®) ) after co-medication with verapamil in healthy subjects.
abstract: OBJECTIVE
  To investigate the effect of the P-glycoprotein inhibitor verapamil on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DE).
  
  
  METHODS
  In this two part multiple crossover trial in 40 healthy subjects, DE 150 mg was given alone or with verapamil at different doses, duration of treatment (single vs. multiple dosing), formulations, and timings (before, concurrently or after DE). Primary pharmacokinetic endpoints were determined from concentrations of total dabigatran (unconjugated plus conjugated). Pharmacodynamic endpoints were determined from clotting time.
  
  
  RESULTS
  The greatest effect was observed with single dose verapamil 120 mg immediate release given 1 h before single dose DE. Geometric mean area under the plasma concentration curve [AUC(0,∞)] and maximum analyte concentration in the plasma (Cmax ) were increased by 143% [90% confidence interval (CI) 91, 208] and 179% (90% CI 115, 262), respectively. The effect was reduced to a 71% and 91% increase in AUC and Cmax , respectively, when DE was administered with verapamil 240 mg extended release. After multiple verapamil dosing, DE AUC(0,∞) and Cmax increases were 54% and 63%, respectively. However, DE given 2 h before verapamil increased DE AUC(0,∞) and Cmax by <20%. With regard to clotting prolongation, the dabigatran plasma concentration-effect relationship was generally not affected by the co-administration of verapamil. Concomitant administration of DE and verapamil did not reveal any unexpected safety findings.
  
  
  CONCLUSIONS
  Verapamil increased DE bioavailability, likely due to inhibition of P-glycoprotein. Our results suggest that an interaction between verapamil and DE can be minimized if DE is administered 2 h prior to verapamil.
authors.affiliation: Boehringer Ingelheim Pharma GmbH, Biberach, Germany. sebastian.haertter@boehringer-ingelheim.com
authors.forename: Sebastian
authors.initials: S
authors.lastname: Härtter
authors.forename: Regina
authors.initials: R
authors.lastname: Sennewald
authors.forename: Gerhard
authors.initials: G
authors.lastname: Nehmiz
authors.forename: Paul
authors.initials: P
authors.lastname: Reilly
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D001777:Blood Coagulation / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D018592:Cross-Over Studies; D000069604:Dabigatran; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013997:Time Factors; D014700:Verapamil / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D003692:Delayed-Action Preparations; D005343:Fibrinolytic Agents; D011725:Pyridines; D014700:Verapamil; D000069604:Dabigatran