PK/PD modeling and optimization of eltrombopag dose and regimen for treatment of chemotherapy-induced thrombocytopenia (CIT) in cancer patients
Siobhan Hayes (1), Paul N Mudd Jr (2), Daniele Ouellet (2), Ekaterina Gibiansky (3)
(1) ICON Development Solutions, Marlow, Buckinghamshire, UK; (2) GlaxoSmithKline, Research Triangle Park, NC, USA; (3) QuantPharm LLC, North Potomac, MD, US
Objectives: To characterize the time course of platelet counts (PLC) following eltrombopag administration, an oral thrombopoietin receptor agonist, in cancer patients receiving carboplatin/paclitaxel (CP), and to optimize eltrombopag dose and regimen for patients receiving CP.
Methods: Of 172 patients undergoing chemotherapy with CP every 21 days, 125 also received 50, 75 or 100 mg eltrombopag for 10 days following each CP administration, and 47 received placebo. Nonlinear mixed effects modeling was used to develop the PK/PD model of PLC reduction due to chemotherapy in patients receiving placebo and to describe the effect of eltrombopag on PLC. Proposed models employed a bone marrow precursor production compartment with first- or zero-order proliferation rate that did or did not depend on PLC, differing number of transit/maturation compartments, and a circulation compartment [1,2]; CP decreased the precursor production rate while eltrombopag increased it. CP concentrations were not collected and were described using a KPD approach . Individual predictions of eltrombopag concentrations were computed using an earlier developed PK model . After visual predictive check evaluation, the final model was used to simulate various eltrombopag dosing regimens with dosing before and after CP.
Results: PLC were described by a 4-compartment model (with thrombopoesis parameters equal to those in healthy subjects ) where carboplatin  and eltrombopag affected zero-order production of platelet precursors. Carboplatin lowered production linearly with dose, more with each cycle, decreasing it by 18.1 to 31.4% at 536 mg of carboplatin (median dose in cycle 1) in cycles 1 to 8, respectively. Eltrombopag stimulated production, linearly with concentration, less with each cycle, increasing it 133 to 37% at 7 mg/mL of eltrombopag concentration (median average concentration at steady state at 100 mg dose) in cycles 1 to 8, respectively, compared to CP alone. Simulations indicated that eltrombopag started 5 days before CP and continued 5 days after in each cycle minimizes the reduction and fluctuation of PLC. Eltrombopag dose should be increased across cycles to overcome the impact of CP, and higher starting doses are required in patients with low baseline PLC.
Conclusions: The developed semi-mechanistic PKPD model described the opposing effects of CP and eltrombopag on PLC, and was used to optimize eltrombopag dose and regimen selection in patients receiving eltrombopag for the treatment of CIT.
 Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of Chemotherapy-Induced Myelosuppression With Parameter Consistency Across Drugs. Journal of Clinical Oncology, 2002, 20(24) 4713-4721.
 Hayes S, Ouellet D, Zhang J, Wire M, Gibiansky E. Population PK/PD Modeling of Eltrombopag in Healthy Volunteers and Patients with Immune Thrombocytopenic Purpura and Optimization of Response-Guided Dosing, J Clin Pharmacol, (2011) 51(10): 1403-1417.
 Jacqmin P, Snoeck E, van Schaick EA, Gieschke R, Pillai P, Steimer JL et al. Modelling Response Time Profiles in the Absence of Drug Concentrations: Definition and Performance Evaluation of the K-PD Model. J Pharmacokinet Pharmacodyn, 2007, 34(1): 57-85.
 Gibiansky E, Mudd P Jr, Kamel Y, Population Pharmacokinetics of Eltrombopag in Patients with Cancer and Healthy Subjects, AAPS Annual Meeting (2009).
 Joerger M, Huitema ADR, Richel DJ, Dittrich C, Pavlidis N, Briasoulis E et al. Population Pharmacokinetics and Pharmacodynamics of Paclitaxel and Carboplatin in Ovarian Cancer Patients: A Study by the European Organization for Research and Treatment of Cancer-Pharmacology and Molecular Mechanisms Group and New Drug Development Group. Clin Cancer Res, 2007, 13(21): 6410-6418.