Population pharmacokinetics of eltrombopag in healthy subjects and patients with chronic idiopathic thrombocytopenic purpura

J Clin Pharmacol. 2011 Jun;51(6):842-56. doi: 10.1177/0091270010375427. Epub 2010 Jul 27.

Abstract

The population pharmacokinetics of eltrombopag were characterized in healthy subjects (n = 111) and patients with idiopathic thrombocytopenic purpura (ITP) (n = 88) using nonlinear mixed-effects modeling. The final model was evaluated via graphical diagnostics and through predictive check and nonparametric bootstrap procedures. A 2-compartment model with dual sequential first-order absorption, absorption lag time, and interoccasion variability in absorption adequately described the data. For a typical 70-kg Caucasian male ITP patient not taking corticosteroids, estimated parameters were apparent clearance (CL/F) = 0.668 L/h, apparent volume of the central compartment (Vc/F) = 8.76 L, apparent volume of the peripheral compartment (Vp/F) = 11.3 L, and distributional clearance (Q/F) = 0.399 L/h. Eltrombopag CL/F, Vc/F, Q/F, and Vp/F increased with body weight. For the range of weights included (43-122 kg), the parameters ranged from 26% lower to 41% higher than for a 70-kg individual. The typical eltrombopag CL/F was 33% lower in East Asians compared with other races, 26% lower in patients taking corticosteroids concomitantly, 19% lower in females compared with males, and 17% higher in healthy subjects compared with ITP patients. There was also a dose effect, with CL/F and Vc/F estimated to be respectively 68% and 55% higher for doses 20 mg or less. In conclusion, East Asian race had the largest impact on eltrombopag exposure with a lower initial dose being recommended.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Asian People / statistics & numerical data
  • Benzoates / administration & dosage
  • Benzoates / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Hydrazines / administration & dosage
  • Hydrazines / pharmacokinetics*
  • Male
  • Middle Aged
  • Models, Statistical*
  • Purpura, Thrombocytopenic, Idiopathic / blood
  • Purpura, Thrombocytopenic, Idiopathic / drug therapy*
  • Pyrazoles / administration & dosage
  • Pyrazoles / pharmacokinetics*
  • Receptors, Thrombopoietin / agonists*
  • Sex Characteristics
  • White People / statistics & numerical data

Substances

  • Benzoates
  • Hydrazines
  • Pyrazoles
  • Receptors, Thrombopoietin
  • MPL protein, human
  • eltrombopag