title: A randomized, open-label, 5-period, balanced crossover study to evaluate the relative bioavailability of eltrombopag powder for oral suspension (PfOS) and tablet formulations and the effect of a high-calcium meal on eltrombopag pharmacokinetics when administered with or 2 hours before or after PfOS.
abstract: BACKGROUND
  Bioavailability of the tablet formulation of eltrombopag, an oral thrombopoietin receptor agonist indicated for the treatment of chronic immune thrombocytopenia, is reduced by chelation of polyvalent cations (eg, calcium). A powder for oral suspension (PfOS) formulation has been developed for use in pediatrics.
  
  
  OBJECTIVE
  We aimed to assess the bioavailability of eltrombopag PfOS relative to the tablet formulation and the effect of a high-calcium meal on PfOS bioavailability.
  
  
  METHODS
  In this single-dose, open-label, randomized-sequence, crossover study, healthy subjects received 25 mg eltrombopag orally as a tablet fasted and as PfOS fasted or with, 2 hours before, or 2 hours after a high-calcium meal. Noncompartmental pharmacokinetic parameters were estimated from plasma concentration-time data collected over 72 hours post-dose. Tolerability was assessed by laboratory tests, physical examinations, and adverse events (AEs).
  
  
  RESULTS
  The 40 enrolled subjects included 22 males and 18 females of white/European (60%) or African-American/African (40%) heritage with mean (SD) (mininum, maximum) age of 34 (12) (19, 62) years, weight of 75 (12) (54, 101) kg, and body mass index of 25.8 (2.9) (19.7, 30) kg/m(2). Plasma eltrombopag AUC(0-∞) was higher for the PfOS than the tablet (geometric least-squares mean ratio [GMR]: 1.22; 90% CI: 1.08-1.38). Plasma eltrombopag AUC(0-∞) was reduced when the PfOS was administered with a high-calcium meal (GMR: 0.25; 90% CI: 0.224-0.287) or 2 hours after a meal (GMR: 0.53; 90% CI: 0.470-0.601), and, to a lesser extent, when administered 2 hours before a meal (GMR: 0.80; 90% CI: 0.711-0.908). The absorption lag time and t(½) did not differ between treatments; T(max) was delayed 1 hour when the PfOS was dosed with a high-calcium meal. AEs were not serious and mild or moderate in intensity. AEs reported in >1 subject included headache (11 subjects; 27.5%), presyncope (3 subjects, 7.5%), and vomiting (2 subjects, 5%). No clinically significant trends in laboratory tests or vital signs were observed.
  
  
  CONCLUSIONS
  In a healthy adult volunteer population, bioavailability of eltrombopag PfOS was greater than the tablet and was reduced when administered with or 2 hours before or after a high-calcium meal; this effect was attenuated with PfOS dosing 2 hours before the meal. Eltrombopag was generally well tolerated.
authors.affiliation: Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline Research and Development, Five Moore Drive, 17.1356F.2B, Research Triangle Park, NC27709, USA. mary.b.wire@gsk.com
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Wire
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bruce
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gauvin
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Pendry
authors.forename: Sandra
authors.initials: S
authors.lastname: McGuire
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Qian
authors.forename: Andres
authors.initials: A
authors.lastname: Brainsky
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001565:Benzoates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D002118:Calcium / Q000378:metabolism*; D018592:Cross-Over Studies; D005260:Female; D005502:Food; D018565:Food-Drug Interactions; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011208:Powders; D011720:Pyrazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D053628:Receptors, Thrombopoietin / Q000819:agonists; D013535:Suspensions; D013607:Tablets; D013997:Time Factors; D055815:Young Adult
chemical_list: D001565:Benzoates; D006834:Hydrazines; D011208:Powders; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; D013535:Suspensions; D013607:Tablets; C082218:MPL protein, human; C520809:eltrombopag; D002118:Calcium