Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 6, pp 1507–1520

Population PK/PD modeling of eltrombopag in subjects with advanced solid tumors with chemotherapy-induced thrombocytopenia

Authors

  • Siobhan Hayes
    • ICON Development Solutions
  • Paul N. MuddJr.
    • GlaxoSmithKline
  • Daniele Ouellet
    • GlaxoSmithKline
  • Brendan M. Johnson
    • GlaxoSmithKline
  • Daphne Williams
    • GlaxoSmithKline
    • Bristol Myers Squibb
    • QuantPharm LLC
Original Article

DOI: 10.1007/s00280-013-2150-9

Cite this article as:
Hayes, S., Mudd, P.N., Ouellet, D. et al. Cancer Chemother Pharmacol (2013) 71: 1507. doi:10.1007/s00280-013-2150-9

Abstract

Purpose

Eltrombopag, a thrombopoietin receptor agonist, is being evaluated for the treatment of chemotherapy-induced thrombocytopenia. Due to the delay in platelet response after the administration of eltrombopag or chemotherapy, a modeling and simulation approach was used to optimize the eltrombopag dosing regimen.

Methods

Pharmacokinetic (PK) data from 2 studies in healthy subjects and PK and platelet data from a Phase II study in subjects with cancer receiving carboplatin/paclitaxel (where eltrombopag was given 10 days after chemotherapy) were used to develop a nonlinear mixed-effects PK/PD model. Alternative eltrombopag dosing regimens were then simulated.

Results

The PK model was a linear two-compartment model with first-order absorption. Being Asian, female, and >50 years of age were associated with higher eltrombopag exposure. The time course of platelet counts was described by a four-compartment transit model. Carboplatin inhibited platelet precursor production linearly with dose, with increased effect with each cycle of chemotherapy. Eltrombopag stimulated platelet precursor production, proportional to plasma eltrombopag concentration, and stimulation (slope of the concentration effect) was attenuated with each cycle of chemotherapy.

Conclusions

Simulations indicated that eltrombopag administered 5 days before and 5 days after chemotherapy minimizes the decrease and fluctuations in platelet counts relative to other evaluated dosing regimens.

Keywords

Platelet countsChemotherapy-induced thrombocytopeniaPopulation pharmacokinetic/pharmacodynamics modelSchedule optimization

Supplementary material

280_2013_2150_MOESM1_ESM.doc (33 kb)
Supplementary material 1 (DOC 33 kb)
280_2013_2150_MOESM2_ESM.doc (166 kb)
Supplementary material 2 (DOC 166 kb)
280_2013_2150_MOESM3_ESM.doc (64 kb)
Supplementary material 3 (DOC 64 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013