title: Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa.
abstract: OBJECTIVE
  Apixaban is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. The effects of rifampin, a strong inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics of oral and intravenous apixaban were evaluated in an open-label, randomized, sequential crossover study.
  
  
  METHODS
  Twenty healthy participants received single doses of apixaban 5 mg intravenously on day 1 and 10 mg orally on day 3, followed by rifampin 600 mg once daily on days 5-15. Finally, participants received single doses of apixaban 5 mg intravenously and 10 mg orally separately on days 12 and 14 in one of two randomized sequences.
  
  
  RESULTS
  Apixaban, given intravenously and orally, was safe and well tolerated when administered in the presence and absence of rifampin. Apixaban absolute oral bioavailability was 49 % when administered alone and 39 % following induction by rifampin. Rifampin reduced apixaban area under the plasma concentration-time curve from time zero to infinity (AUC∞) by 39 % after intravenous administration and by 54 % after oral administration. Rifampin induction increased mean clearance by 1.6-fold for intravenous apixaban and mean apparent clearance by 2.1-fold for oral apixaban, indicating rifampin affected both pre-systemic and systemic apixaban elimination pathways.
  
  
  CONCLUSIONS
  Co-administration of apixaban with rifampin reduced apixaban exposure via both decreased bioavailability and increased systemic clearance.
authors.affiliation: Research and Development, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Mail Stop E12-16, Route 206 and Province Line Road, Princeton, NJ, 08543-4000, USA.
authors.forename: Blisse
authors.initials: B
authors.lastname: Vakkalagadda
authors.affiliation: Research and Development, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Mail Stop E12-16, Route 206 and Province Line Road, Princeton, NJ, 08543-4000, USA. charles.frost@bms.com.
authors.forename: Charles
authors.initials: C
authors.lastname: Frost
authors.affiliation: Global Innovative Pharma Business Clinical Pharmacology, Pfizer Inc, Groton, CT, USA.
authors.forename: Wonkyung
authors.initials: W
authors.lastname: Byon
authors.affiliation: Global Innovative Pharma Business Clinical Pharmacology, Pfizer Inc, Groton, CT, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Boyd
authors.affiliation: Global Biometric Sciences, Bristol-Myers Squibb Company, Princeton, NJ, USA.
authors.forename: Jessie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, NJ, USA.
authors.forename: Donglu
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Research and Development, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Mail Stop E12-16, Route 206 and Province Line Road, Princeton, NJ, 08543-4000, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Research and Development, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Mail Stop E12-16, Route 206 and Province Line Road, Princeton, NJ, 08543-4000, USA.
authors.forename: Clapton
authors.initials: C
authors.lastname: Dias
authors.affiliation: Research and Development, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Mail Stop E12-16, Route 206 and Province Line Road, Princeton, NJ, 08543-4000, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Shenker
authors.affiliation: Research and Development, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Mail Stop E12-16, Route 206 and Province Line Road, Princeton, NJ, 08543-4000, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: LaCreta
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D065427:Factor Xa Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D011720:Pyrazoles / Q000493:pharmacokinetics*; D011728:Pyridones / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin