title: Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers.
abstract: OBJECTIVE
  Interactions between ticagrelor and atorvastatin or simvastatin were investigated in two-way crossover studies.
  
  
  METHODS
  Both studies were open-label for statin; the atorvastatin study was placebo-controlled for ticagrelor. For atorvastatin, volunteers (n = 24) received ticagrelor (loading dose 270 mg; 90 mg twice daily, 7 days) or placebo, plus atorvastatin calcium (80 mg; day 5). For simvastatin, volunteers (n = 24) received simvastatin 80 mg, or ticagrelor (loading dose 270 mg; 180 mg twice daily, 7 days) plus simvastatin (80 mg; day 5). In each study, volunteers received the alternate treatment after washout (≥ 7 days).
  
  
  RESULTS
  Ticagrelor increased mean atorvastatin maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from zero to infinity (AUC) by 23 % and 36 %, respectively. Simvastatin C(max) and AUC were increased by 81 % and 56 % with ticagrelor. Ticagrelor also increased C(max) and AUC of analysed atorvastatin metabolites by 13-55 % and 32-67 %, respectively, and simvastatin acid by 64 % and 52 %, respectively. Co-administration of ticagrelor with each statin was well tolerated.
  
  
  CONCLUSIONS
  Exposure to ticagrelor and its active metabolite, AR-C124910XX, was generally unchanged by a single dose of either statin, except for a minor increase in ticagrelor C(max) in the presence of simvastatin. Effects of ticagrelor on atorvastatin pharmacokinetics were modest and unlikely clinically relevant, while with simvastatin, changes were slightly larger, and simvastatin doses >40 mg with ticagrelor should be avoided.
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 D
authors.initials: PD
authors.lastname: Mitchell
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Butler
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D019540:Area Under Curve; D000069059:Atorvastatin; D001711:Biotransformation; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006207:Half-Life; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016018:Least-Squares Analysis; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000077486:Ticagrelor
chemical_list: C561701:AR C124910XX; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin; D000077486:Ticagrelor; D000241:Adenosine