title: Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: two single-dose, open-label, randomized-sequence, crossover studies.
abstract: BACKGROUND
  Eltrombopag is the first orally self-administered, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura.
  
  
  OBJECTIVE
  The aim of these studies was to assess the effect of food and antacids on the pharmacokinetic and safety profiles of eltrombopag.
  
  
  METHODS
  Two independent, single-dose, open-label, randomized-sequence, crossover studies of oral eltrombopag were conducted in healthy adult volunteers. The first study (study A) compared eltrombopag 50 mg (tablets or capsules) administered in the fasted state or tablets with a high-fat, high-calcium breakfast. The second study (study B) investigated eltrombopag tablets (75 mg) administered in the fasted state; immediately after a low-fat, low-calcium meal or a high-fat, low-calcium meal; 1 hour before a high-fat, low-calcium meal; or with an antacid containing aluminum hydroxide and magnesium carbonate. Vital signs were recorded and electrocardiogram and clinical laboratory tests were performed at screening, within 24 hours before and within 48 hours after each dose of study medication. Symptom assessment was performed and adverse events (AEs) were assessed previous to study drug administration through follow-up in terms of severity and relationship to study medication.
  
  
  RESULTS
  In study A, 18 male subjects (mean age, 23.0 years; weight, 70.3 kg; white race, 94.4%) who received a high-fat, high-calcium breakfast had reduced bioavailability of eltrombopag in terms of AUC(0-infinity)) by 59% (geometric mean ratio [GMR], 0.41; 90% CI, 0.36-0.46) and C(max) by 65% (GMR, 0.35; 90% CI, 0.30-0.41) compared with subjects in a fasted state. In study B, the bioavailability in 26 subjects (14 male, 12 female; mean age, 35.6 years; weight, 76.0 kg; white race, 65.4%) was not significantly changed when administered with food that was low in calcium, despite the fat content (GMRs ranged from 0.87-1.03 for AUC(0-infinity) and 0.85-1.01 for C(max) across the 3 studied meals). Mean plasma AUC(0-infinity)) and C(max) values decreased by approximately 70% (GMR, 0.30; 90% CI, 0.24-0.36 for AUC(0-infinity)) and 0.24-0.38 for C(max)) when administered with a metal cation-containing antacid. No serious AEs were reported and all AEs were rated as mild to moderate in intensity. The most frequently reported AE was headache (study A, 6.3%; study B, 12.0%-29.2%).
  
  
  CONCLUSIONS
  Concomitant administration of eltrombopag with high-calcium food or an antacid containing aluminum and magnesium was associated with significantly reduced systemic exposure, whereas low-calcium meals were not. A single dose of eltrombopag was generally well tolerated in these healthy volunteers.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Daphne D
authors.initials: DD
authors.lastname: Williams
authors.forename: Bin
authors.initials: B
authors.lastname: Peng
authors.forename: Christine K
authors.initials: CK
authors.lastname: Bailey
authors.forename: Mary B
authors.initials: MB
authors.lastname: Wire
authors.forename: Yanli
authors.initials: Y
authors.lastname: Deng
authors.forename: Jung Wook
authors.initials: JW
authors.lastname: Park
authors.forename: David A
authors.initials: DA
authors.lastname: Collins
authors.forename: Shiva G
authors.initials: SG
authors.lastname: Kapsi
authors.forename: Julian M
authors.initials: JM
authors.lastname: Jenkins
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000536:Aluminum Hydroxide / Q000494:pharmacology; D000863:Antacids / Q000494:pharmacology*; D019540:Area Under Curve; D001565:Benzoates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D002136:Calcium, Dietary / Q000494:pharmacology; D002214:Capsules; D018592:Cross-Over Studies; D004041:Dietary Fats / Q000494:pharmacology; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D053628:Receptors, Thrombopoietin / Q000819:agonists; D013607:Tablets; D055815:Young Adult
chemical_list: D000863:Antacids; D001565:Benzoates; D002136:Calcium, Dietary; D002214:Capsules; D004041:Dietary Fats; D004338:Drug Combinations; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; D013607:Tablets; C005479:magnesium carbonate; D000536:Aluminum Hydroxide; D008274:Magnesium; C520809:eltrombopag