Dataset Information

Oral bioavailability of dabigatran etexilate (Pradaxa(®) ) after co-medication with verapamil in healthy subjects.

ABSTRACT:

Aim

To investigate the effect of the P-glycoprotein inhibitor verapamil on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DE).

Method

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.

Conclusion

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.

SUBMITTER: Hartter S

PROVIDER: S-EPMC3612723 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Publications

Oral bioavailability of dabigatran etexilate (Pradaxa(®) ) after co-medication with verapamil in healthy subjects.

Härtter Sebastian S Sennewald Regina R Nehmiz Gerhard G Reilly Paul P

British journal of clinical pharmacology 20130401 4

<h4>Aim</h4>To investigate the effect of the P-glycoprotein inhibitor verapamil on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DE).<h4>Method</h4>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 dabigatr ...[more]

PMID: 22946890

Similar Datasets

Project description:Background and objectiveDabigatran etexilate (DE) is an anticoagulant with proven efficacy and tolerability for stroke prevention in patients with non-valvular atrial fibrillation. For the commercial capsule, a complex formulation is used to maintain the acidic microenvironment required for maximal absorption. Consequently, its efficacy and safety are similar with or without concomitant intake of proton-pump inhibitors (PPIs). A simplified DE tablet formulation was developed and tested in two studies. One investigated bioequivalence (BE) of the novel DE tablet versus the commercial DE capsule. The other investigated DE bioavailability (BA) under pretreatment with the PPI rabeprazole and assessed the effect of elevated pH on exposure to dabigatran.MethodsBE of the novel DE tablet versus the DE capsule was assessed in a randomized two-treatment, four-period, two-sequence crossover study (NCT03070171). The effect of rabeprazole on the BA of the DE tablet was assessed in an open-label, single-arm study (NCT03143166). Both studies were conducted at sites in Japan. Participants were healthy male volunteers, aged ≥ 20-40 years. In the BE study, participants received the DE tablet or capsule (single oral dose, 110 mg); primary endpoints were area under the concentration-time curve from baseline to the last quantifiable data point (AUC0-tz) and maximum plasma concentration (Cmax) of unconjugated dabigatran. In the relative BA study, participants received the DE tablet (single oral dose, 110 mg) with or without rabeprazole pretreatment (once daily for 5 days, 20 mg); primary endpoints were AUC0-tz and Cmax of total dabigatran.ResultsIn total, 160 participants were randomized in the BE study; 36 participants were enrolled in the BA study. The 90% confidence intervals of geometric mean (gMean) ratios for AUC0-tz (101.4-116.0%) and Cmax (101.8-116.6%) of unconjugated dabigatran were within pre-defined acceptance criteria for BE. In the relative BA study, the gMeans of AUC0-tz (667 to 192 ng h/mL) and Cmax (83.1 to 21.8 ng/mL) were decreased by approximately 70% when the tablet was administered under rabeprazole pretreatment. The reduction in BA was observed at a mean gastric pH of 5.3. Treatment was well tolerated; no deaths, serious adverse events (AEs) or significant AEs were reported in either study.ConclusionThe DE tablet demonstrated BE to the capsule; however, at high gastric pH, BA of the tablet was reduced by approximately 70%, which may lead to reduced efficacy. Data indicate the importance of examining not only BE under standard conditions, but relative BA at elevated gastric pH. Such investigations may avoid the reduced BA at elevated pH that is quite common in the target population (the elderly and/or patients treated with gastric-acid modifying co-medications), and therefore reduce treatment failure with DE. Registration: ClinicalTrials.gov identifier numbers: NCT03070171, and NCT03143166.

Dataset Information

Oral bioavailability of dabigatran etexilate (Pradaxa(®) ) after co-medication with verapamil in healthy subjects.

Aim

Method

Results

Conclusion

Publications

Oral bioavailability of dabigatran etexilate (Pradaxa(®) ) after co-medication with verapamil in healthy subjects.

Similar Datasets

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