Modeling and Simulation Support Eltrombopag Dosing in Thrombocytopenic Patients with Chronic HCV Infection
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The pharmacokinetics of eltrombopag and its stimulation of platelet production were characterized in patients with chronic hepatitis C virus (HCV) infection to optimize an eltrombopag dosing regimen for treatment of HCV-related thrombocytopenia before and throughout peginterferon (pegIFN)-based antiviral therapy.
Population pharmacokinetic analysis for eltrombopag included 663 individuals (healthy subjects, n = 28; patients with HCV, n = 635). Population pharmacokinetic/pharmacodynamic analysis for platelet response involved patients with HCV only. Simulations were conducted using various dosing scenarios in the same patient population.
Eltrombopag pharmacokinetics were described by a two-compartment model with dual sequential first-order absorption and elimination. Age, race, sex, and severity of hepatic impairment were predictors of eltrombopag clearance. The effect of eltrombopag on platelet counts was adequately described by a model with four transit compartments in which eltrombopag concentrations stimulated the production rate of platelet precursors in an Emax manner.
Modeling and simulation results support once-daily eltrombopag 25 mg as an appropriate starting dosing regimen followed by biweekly dose escalation (in 25-mg increments) up to once-daily eltrombopag 100 mg to raise platelet counts sufficiently for initiation of pegIFN-based antiviral therapy in patients with HCV. Biweekly dose adjustment allows patients to stay on the lowest possible eltrombopag dose during antiviral therapy.
KEY WORDSEltrombopag hepatitis C virus platelet counts population pharmacokinetic/pharmacodynamic thrombocytopenia
Baseline platelet count
Chronic liver disease
Direct-acting antiviral agent
Hepatitis C virus
Production rate of platelet precursors
Maturation rate of platelet precursors
Linear effect of pegIFN concentrations on platelet production
Apparent central volume of distribution
Visual predictive check
Apparent peripheral volume of distribution
ACKNOWLEDGMENTS AND DISCLOSURES
All listed authors meet the criteria for authorship set forth by the International Committee of Medical Journal Editors. M.T. and C.F. have nothing to disclose. J.Z. and M.B.W. are employees of and hold stock in GlaxoSmithKline (GSK). Funding for this analysis was provided by GSK. All authors were involved in the analysis and interpretation of the data, and approval of the manuscript for publication. Editorial assistance was provided by AOI Communications, L.P., which was funded by GSK.
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