title: Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers.
abstract: BACKGROUND
  OATP1B1 is important for hepatic uptake of rosuvastatin and BCRP is important for rosuvastatin absorption and elimination. Eltrombopag inhibits OATP1B1 and BCRP in vitro at clinically relevant concentrations. Inhibition of these transporters could change cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects.
  
  
  CONCLUSIONS
  Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure via inhibition of drug transporters. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed.
  
  
  OBJECTIVE
  Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, inhibits the organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) in vitro. OATP1B1 is important for hepatic uptake of rosuvastatin and inhibition of this transporter could reduce cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. In contrast, BCRP is an efflux transporter and inhibition of this transporter could increase both hepatic and plasma rosuvastatin concentrations, resulting in increased efficacy and toxicity. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects.
  
  
  METHODS
  Subjects received rosuvastatin and eltrombopag orally: day 1, rosuvastatin 10 mg single dose; days 6 to 9, eltrombopag 75 mg once daily; day 10, eltrombopag 75 mg once daily and rosuvastatin 10 mg single dose. Adverse event assessments were performed daily and at the follow-up visit. Plasma samples for pharmacokinetic analysis were collected days 1 to 5 and days 10 to 14.
  
  
  RESULTS
  Co-administration of eltrombopag with rosuvastatin increased geometric mean (90% confidence interval) plasma rosuvastatin AUC(0,∞) by 55% (42%, 69%) and C(max) by 103% (82%, 126%) in the overall study population, with a larger interaction in the non-Asian compared with Asian subjects.
  
  
  CONCLUSIONS
  Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed.
authors: GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC, USA.
authors: Alicia J
authors: AJ
authors: Allred
authors: Carolyn J
authors: CJ
authors: Bowen
authors: Jung Wook
authors: JW
authors: Park
authors: Bin
authors: B
authors: Peng
authors: Daphne D
authors: DD
authors: Williams
authors: Mary Beth
authors: MB
authors: Wire
authors: Edmund
authors: E
authors: Lee
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000328:Adult; D001565:Benzoates / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D006801:Humans; D006834:Hydrazines / Q000493:pharmacokinetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D011720:Pyrazoles / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000493:pharmacokinetics*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001565:Benzoates; D005464:Fluorobenzenes; D006834:Hydrazines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D011720:Pyrazoles; D011743:Pyrimidines; D053628:Receptors, Thrombopoietin; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; C520809:eltrombopag