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

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Hartter S, Sennewald R, Nehmiz G, Reilly P

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

Br J Clin Pharmacol. 2013 Apr;75(4):1053-62. doi: 10.1111/j.1365-2125.2012.04453.x.

PubMed ID

22946890 [ View in PubMed

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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,infinity)] 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,infinity) and Cmax increases were 54% and 63%, respectively. However, DE given 2 h before verapamil increased DE AUC(0,infinity) 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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Dabigatran etexilate	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details

Drug Interactions

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drugs	Interaction
Integrate drug-drug interactions in your software
Dabigatran etexilate Verapamil	The serum concentration of Dabigatran etexilate can be increased when it is combined with Verapamil.
Dabigatran etexilate Norgestimate	The serum concentration of Dabigatran etexilate can be increased when it is combined with Norgestimate.
Dabigatran etexilate Fluconazole	The serum concentration of Dabigatran etexilate can be increased when it is combined with Fluconazole.
Dabigatran etexilate Erythromycin	The serum concentration of Dabigatran etexilate can be increased when it is combined with Erythromycin.
Dabigatran etexilate Sildenafil	The serum concentration of Dabigatran etexilate can be increased when it is combined with Sildenafil.