Coadministration of dabigatran (150 mg single dose) with ritonavir (100 mg, once daily, n=16) was studied in healthy volunteers in a cross-over study. Dabigatran was given either 2 hours before or simultaneously with ritonavir. There were no statistically significant changes to dabigatran AUC or Cmax when dabigatran was coadministered simultaneously with ritonavir. However, dabigatran AUC and Cmax decreased by 29% and 27%, respectively, when coadministered separately to ritonavir. There were no significant changes to thrombin time in either arm of the ritonavir study. The authors hypothesise that no significant effect on dabigatran pharmacokinetics was seen with ritonavir due to its mixed induction and inhibitory effect on P-gp.

The interaction between dabigatran and the P-gp inhibitor verapamil was simulated using physiologically based pharmacokinetic modelling (PBPK) in virtual individuals with a normal renal function (CrCl >80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl 30-50 mL/min) and severe (CrCl 15-30 mL/min) renal impairment. In individuals with normal renal function, predicted Ctrough were within dabigatran therapeutic range (28-210 ng/ml) when dabigatran was administered concurrently with or 2 hours before verapamil at a dose of 150 mg twice daily. However, Ctrough was below the lower limit of the therapeutic range when dabigatran was administered at 110 mg twice daily 2 hours before verapamil but still within the therapeutic range in case of simultaneous administration. In individuals with mild renal impairment, predicted Ctrough exceeded the upper limit of the therapeutic range when dabigatran was administered concurrently or 2 hours before verapamil at a dose of 150 mg twice daily but were within the therapeutic range when administered at a dose of 110 mg twice daily. In individuals with moderate renal impairment, predicted Ctrough exceeded the upper limit of the therapeutic range when dabigatran was administered concurrently with and 2 hours before verapamil at a dose of 110 mg twice daily but were within the therapeutic range when administered at a dose of 75 mg twice daily. Finally, in individuals with severe renal impairment, predicted Ctrough exceeded the upper limit of the therapeutic range when dabigatran was administered concurrently with verapamil at a dose of 75 mg twice daily. This study indicates that dabigatran dosage in presence of a P-gp inhibitor such as verapamil varies depending on the renal function. These results suggest that, when coadministered with verapamil, one (110 mg twice daily) and two-stage (75 mg twice daily) reductions of the dabigatran dose are required for individuals with mild and moderate renal impairment, respectively.