Population PK/PD modeling of eltrombopag in subjects with advanced solid tumors with chemotherapy-induced thrombocytopenia
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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.
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.
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.
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.
KeywordsPlatelet counts Chemotherapy-induced thrombocytopenia Population pharmacokinetic/pharmacodynamics model Schedule optimization
Clinical trials described in this work were funded by GlaxoSmithKline. Paul N. Mudd Jr., Daniele Ouellet, and Brendan M. Johnson are GSK employees. Ekaterina Gibiansky and Siobhan Hayes were consultants for GSK.
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