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

Clin Ther. 2012 Mar;34(3):699-709. doi: 10.1016/j.clinthera.2012.01.011. Epub 2012 Feb 14.


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.

Trial registration: ClinicalTrials.gov NCT01072162.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Benzoates / administration & dosage
  • Benzoates / blood
  • Benzoates / pharmacokinetics*
  • Benzoates / pharmacology
  • Biological Availability
  • Calcium / metabolism*
  • Cross-Over Studies
  • Female
  • Food*
  • Food-Drug Interactions*
  • Humans
  • Hydrazines / administration & dosage
  • Hydrazines / blood
  • Hydrazines / pharmacokinetics*
  • Hydrazines / pharmacology
  • Male
  • Middle Aged
  • Powders
  • Pyrazoles / administration & dosage
  • Pyrazoles / blood
  • Pyrazoles / pharmacokinetics*
  • Pyrazoles / pharmacology
  • Receptors, Thrombopoietin / agonists
  • Suspensions
  • Tablets
  • Time Factors
  • Young Adult


  • Benzoates
  • Hydrazines
  • Powders
  • Pyrazoles
  • Receptors, Thrombopoietin
  • Suspensions
  • Tablets
  • MPL protein, human
  • eltrombopag
  • Calcium

Associated data

  • ClinicalTrials.gov/NCT01072162