title: Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects.
abstract: OBJECTIVE
  Ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, is predominantly metabolized by cytochrome P450 3A and both the parent compound and its active metabolite AR-C124910XX are substrates of P-glycoprotein. Rifampicin was used to assess the effects of CYP3A and P-glycoprotein induction on the single-dose pharmacokinetics and pharmacodynamics of ticagrelor.
  
  
  METHODS
  Healthy volunteers received a single 180 mg oral dose of ticagrelor on days 1 and 15, and a once-daily 600 mg dose of rifampicin on days 4-17. Ticagrelor and AR-C124910XX plasma concentrations were quantified for pharmacokinetic analysis (n = 14); inhibition of platelet aggregation (IPA) was also assessed (n = 14).
  
  
  RESULTS
  Compared with administration of ticagrelor alone, co-administration of ticagrelor and rifampicin significantly decreased the maximum plasma concentration (Cmax) of ticagrelor from 1091 to 297.8 ng/ml, area under the plasma concentration-time curve from time zero to infinity (AUC) of ticagrelor from 6225 to 864.0 ng.h/ml, and also decreased plasma half-life of ticagrelor from 8.4 to 2.8 h; reductions of 73 %, 86 % and 67 % respectively. With rifampicin, AR-C124910XX Cmax was unaffected, AUC was significantly decreased by 46 %, and metabolite to parent ratio for AUC increased fourfold. Although maximal IPA was unaffected, offset of ticagrelor-mediated IPA was more rapid in the presence of rifampicin; a significant reduction (27 %) in the area under the effect curve between 0 and 24 h was observed following co-administration with rifampicin.
  
  
  CONCLUSIONS
  Co-administration with rifampicin reduced ticagrelor exposure and resulted in a more rapid offset of ticagrelor-mediated IPA. Co-administration of strong CYP3A/P-glycoprotein inducers with ticagrelor should be discouraged.
authors.affiliation: Clinical Pharmacology, AstraZeneca LP, OW3-117, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA. renli.teng@astrazeneca.com
authors.forename: Renli
authors.initials: R
authors.lastname: Teng
authors.forename: Patrick
authors.initials: P
authors.lastname: Mitchell
authors.forename: Kathleen
authors.initials: K
authors.lastname: Butler
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D000077486:Ticagrelor; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D058921:Purinergic P2Y Receptor Antagonists; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D000077486:Ticagrelor; D000241:Adenosine; D012293:Rifampin