Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin

Abstract

Aims: This study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of dabigatran following oral administration of the prodrug, dabigatran etexilate.

Methods: This was an open-label, fixed-sequence, four-period study in healthy volunteers. Subjects received a single dose of dabigatran etexilate 150 mg on day 1, rifampicin 600 mg once daily on days 2-8, and single doses of dabigatran etexilate on days 9, 16 and 23.

Results: Twenty-four subjects were treated, of whom 22 received all treatments. Relative to the reference (single dose of dabigatran etexilate alone; treatment A), administration of dabigatran etexilate following 7 days of rifampicin (treatment B) decreased the geometric mean (gMean) area under the concentration-time curve (AUC(0-∞)) and maximal plasma concentration (C(max)) of total dabigatran by 67 and 65.5%, respectively. The time to peak and the terminal half-life were not affected. The gMean ratio for the primary comparison (treatment B vs. treatment A) was 33.0% (90% confidence interval 26.5, 41.2%) for AUC(0-∞) and 34.5% (90% confidence interval 26.9, 44.1%) for C(max), indicating a significant effect on total dabigatran exposure (total pharmacologically active dabigatran represents the sum of nonconjugated dabigatran and dabigatran glucuronide). After a 7 day (treatment C) or 14 day washout (treatment D), the AUC(0-∞) and C(max) of dabigatran were reduced by 18 and 20%, and by 15 and 20%, respectively, compared with treatment A, which was considered not clinically relevant. The overall safety profile of all treatments was good.

Conclusions: Administration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days washout.

Figure 1

Administration of trial medication (upper half of the diagram) and definition of treatment periods for safety analyses (lower half of the diagram). Dabigatran etexilate was always given in the morning at 08.00 h. Rifampicin was always administered in the evening at 20.00 h, with the last dose given 12 h before the dabigatran etexilate test treatment on day 9. D150, dabigatran etexilate 150 mg; R600, rifampicin 600 mg; D+R, dabigatran etexilate + rifampicin; P2, P3, period 2, period 3.

Figure 2

Geometric mean (gMean) plasma concentration–time profiles (semi-logarithmic scale) of total (a) and free dabigatran (b) after a single oral dose of 150 mg dabigatran etexilate on day 1 (reference; treatment A), on day 9 after administration of multiple doses of 600 mg rifampicin (test 1; treatment B), on day 16, i.e. 7 days after last rifampicin administration (test 2; treatment C) and on day 23, i.e. 14 days after last rifampicin administration (test 3; treatment D). Day 1 (period 1, reference) (N = 24) (); Day 9 (period 2, test) (N = 24) (); Day 16 (period 3, test) (N = 22) (); Day 23 (period 4, test) (N = 22) ()

Figure 3

Intra-individual comparisons of AUC_0–∞ (upper panel) and C_max (lower panel) of total dabigatran after a single oral dose of 150 mg dabigatran etexilate alone on day 1 (treatment A) or 1, 7 or 14 days after the last administration of rifampicin 600 mg once daily given for 7 days (treatments B, C and D; days 9, 16 and 23, respectively). Individual data (); gMean (n = 24/24/22/22) ()