Effect of Food and Pantoprazole on the Bioavailability of the Direct Thrombin Inhibitor Dabigatran in Healthy Subjects

Abstract number: P1612

Stangier J, Stähle H, Rathgen K

Dabigatran etexilate is a direct thrombin inhibitor in clinical development for the prophylaxis of thromboembolic events. After oral administration, the pro-drug dabigatran etexilate is rapidly and completely converted to the active form dabigatran. This study evaluated the pharmacokinetics (PK) of dabigatran after administration of dabigatran etexilate with the proton pump inhibitor pantoprazole or with a high fat, high caloric breakfast. Primary endpoints were the rate and extent of absorption of dabigatran in the fed and fasted state or at elevated gastric pH due to pantoprazole (P) administration. In this single dose, 3-fold crossover trial, 18 healthy male subjects were randomized to 150 mg dabigatran etexilate fasted, 150 mg dabigatran etexilate with food, and 150 mg dabigatran etexilate with P, fasted (2 days pre-treatment with 40 mg P b.i.d). Serial blood samples were collected for calculation of the area under the dabigatran plasma concentration-time curve, AUC. Dabigatran in the fasted state was rapidly absorbed with peak plasma concentrations at 2 hours post dose. After Cmax, plasma concentrations showed a biphasic decline with a terminal half life of 8.5 h (without P) and 7.7 hours (with P). With P co-administration, the dabigatran AUC was reduced by 30%. Interindividual variability of AUC in the fasted state was 44% CV and 56% CV (with P), respectively. Administration of dabigatran etexilate immediately after a high fat, high caloric breakfast increased tmax from 2 h to 4 h. Total drug exposure remained essentially unchanged upon administration of food. AUC increased by about 8% and Cmax by 2% compared to fasted administration. Interindividual variability of AUC in the fed state was low with 21% CV. Single oral doses of 150 mg dabigatran etexilate with/without food or P were well tolerated. The clinical significance of the effect of P remains to be elucidated. It is concluded that dabigatran etexilate may be taken with or without food.