Effect of bosutinib on the absorption of dabigatran etexilate mesylate, a P-glycoprotein substrate, in healthy subjects

Eur J Clin Pharmacol. 2017 Jan;73(1):57-63. doi: 10.1007/s00228-016-2115-0. Epub 2016 Oct 7.


Purpose: Bosutinib, a dual Src and Abl tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, demonstrated concentration-dependent inhibitory effects on P-glycoprotein (P-gp)-mediated digoxin efflux in vitro, suggesting that bosutinib may inhibit P-gp substrates. The effect of bosutinib on dabigatran etexilate mesylate (EM) absorption, a P-gp substrate, was evaluated.

Methods: In this open-label, randomized, single-dose, one-cohort, two-sequence, two-period crossover study, healthy, fed subjects received dabigatran EM (150 mg × 1 orally) alone or 1 h after receiving bosutinib tablets (100 mg × 5 orally).

Results: Dabigatran EM monotherapy and concurrent administration of dabigatran EM with bosutinib resulted in similar values for concentration time curves from time zero extrapolated to infinity (AUCinf), but slightly lower maximum plasma concentration (C max) values (AUCinf, 1182 and 1186 ng·h/mL, respectively; C max, 129.8 and 114.1 ng/mL). The time to maximum concentration for dabigatran was 2.99 and 3.99 h for combination therapy. The ratio of the adjusted geometric means (test/reference) of dabigatran AUCinf and C max (90 % confidence interval) were 101.4 % (89.6-114.9 %) and 89.7 % (77.8-103.4 %), respectively, following administration of dabigatran EM with bosutinib (test) relative to dabigatran EM administered alone (reference). Six subjects receiving combination treatment reported a total of seven adverse events (AEs) versus none for subjects receiving monotherapy alone. All AEs were mild to moderate and considered treatment related.

Conclusion: These data demonstrate that single doses of bosutinib do not affect dabigatran exposure, suggesting that bosutinib is not a clinical inhibitor of P-gp.

Trial registration: ClinicalTrials.gov NCT02102633. https://clinicaltrials.gov/ct2/show/NCT02102633?term=NCT02102633&rank=1.

Keywords: Aprepitant; Bosutinib; Dabigatran; Drug–drug interactions; Pharmacokinetics; Tyrosine kinase inhibitor.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Adult
  • Aniline Compounds / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Antithrombins / adverse effects
  • Antithrombins / blood
  • Antithrombins / pharmacokinetics*
  • Area Under Curve
  • Cross-Over Studies
  • Dabigatran / adverse effects
  • Dabigatran / blood
  • Dabigatran / pharmacokinetics*
  • Drug Interactions
  • Female
  • Healthy Volunteers
  • Humans
  • Intestinal Absorption / drug effects
  • Male
  • Middle Aged
  • Nitriles / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Quinolines / pharmacology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Aniline Compounds
  • Antineoplastic Agents
  • Antithrombins
  • Nitriles
  • Protein Kinase Inhibitors
  • Quinolines
  • bosutinib
  • Dabigatran

Associated data

  • ClinicalTrials.gov/NCT02102633