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

E Gibiansky, J Zhang, D Williams… - The Journal of …, 2011 - Wiley Online Library
E Gibiansky, J Zhang, D Williams, Z Wang, D Ouellet
The Journal of Clinical Pharmacology, 2011Wiley Online Library
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 …
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.
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