PMID- 27717999
OWN - NLM
STAT- MEDLINE
DCOM- 20170227
LR  - 20181202
IS  - 1432-1041 (Electronic)
IS  - 0031-6970 (Linking)
VI  - 73
IP  - 1
DP  - 2017 Jan
TI  - Effect of bosutinib on the absorption of dabigatran etexilate mesylate, a 
      P-glycoprotein substrate, in healthy subjects.
PG  - 57-63
LID - 10.1007/s00228-016-2115-0 [doi]
AB  - 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 x 1 orally) alone or 1 h after receiving bosutinib tablets (100 mg x 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 (AUC(inf)), but slightly lower 
      maximum plasma concentration (C (max)) values (AUC(inf), 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 AUC(inf) 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.
FAU - Hsyu, Poe-Hirr
AU  - Hsyu PH
AD  - Pfizer Inc, 10646 Science Center Drive, La Jolla, CA, 92121, USA. 
      Poe-Hirr.Hysu@pfizer.com.
FAU - Pignataro, Daniela Soriano
AU  - Pignataro DS
AD  - Pfizer Inc, Walton Oaks, Dorking Road, Surrey, KT20 7NS, UK.
FAU - Matschke, Kyle
AU  - Matschke K
AD  - Pfizer Inc, 500 Arcola Road, Collegeville, PA, 19426, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT02102633
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20161007
PL  - Germany
TA  - Eur J Clin Pharmacol
JT  - European journal of clinical pharmacology
JID - 1256165
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Aniline Compounds)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antithrombins)
RN  - 0 (Nitriles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - 5018V4AEZ0 (bosutinib)
RN  - I0VM4M70GC (Dabigatran)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
MH  - Adult
MH  - Aniline Compounds/*pharmacology
MH  - Antineoplastic Agents/*pharmacology
MH  - Antithrombins/adverse effects/blood/*pharmacokinetics
MH  - Area Under Curve
MH  - Cross-Over Studies
MH  - Dabigatran/adverse effects/blood/*pharmacokinetics
MH  - Drug Interactions
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Intestinal Absorption/drug effects
MH  - Male
MH  - Middle Aged
MH  - Nitriles/*pharmacology
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Quinolines/*pharmacology
OTO - NOTNLM
OT  - Aprepitant
OT  - Bosutinib
OT  - Dabigatran
OT  - Drug-drug interactions
OT  - Pharmacokinetics
OT  - Tyrosine kinase inhibitor
EDAT- 2016/10/09 06:00
MHDA- 2017/02/28 06:00
CRDT- 2016/10/09 06:00
PHST- 2016/05/19 00:00 [received]
PHST- 2016/08/05 00:00 [accepted]
PHST- 2016/10/09 06:00 [pubmed]
PHST- 2017/02/28 06:00 [medline]
PHST- 2016/10/09 06:00 [entrez]
AID - 10.1007/s00228-016-2115-0 [pii]
AID - 10.1007/s00228-016-2115-0 [doi]
PST - ppublish
SO  - Eur J Clin Pharmacol. 2017 Jan;73(1):57-63. doi: 10.1007/s00228-016-2115-0. Epub 
      2016 Oct 7.