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Pharmaceutical Research

, Volume 32, Issue 6, pp 2015–2028 | Cite as

Modeling and Simulation Support Eltrombopag Dosing in Thrombocytopenic Patients with Chronic HCV Infection

  • Jianping Zhang
  • Mita Thapar
  • Colm Farrell
  • Mary B. Wire
Research Paper

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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 WORDS

Eltrombopag hepatitis C virus platelet counts population pharmacokinetic/pharmacodynamic thrombocytopenia 

ABBREVIATIONS

AST

Aspartate aminotransferase

BASE

Baseline platelet count

CI

Confidence interval

CL/F

Apparent clearance

CLD

Chronic liver disease

CPS

Child-Pugh score

DAA

Direct-acting antiviral agent

HCV

Hepatitis C virus

IFN

Interferon

KIN

Production rate of platelet precursors

KPD

Kinetic-pharmacodynamic

KT

Maturation rate of platelet precursors

PD

Pharmacodynamics

PegIFN

Pegylated interferon

PK

Pharmacokinetics

RBV

Ribavirin

SLPC

Linear effect of pegIFN concentrations on platelet production

Vc/F

Apparent central volume of distribution

VPC

Visual predictive check

Vp/F

Apparent peripheral volume of distribution

Notes

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.

Supplementary material

11095_2014_1594_MOESM1_ESM.docx (21 kb)
Supplemental Table 1 Summary of Covariate Model Development for Eltrombopag Population PK Model (DOCX 21.2 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Jianping Zhang
    • 1
  • Mita Thapar
    • 2
  • Colm Farrell
    • 2
  • Mary B. Wire
    • 1
  1. 1.Department of Clinical Pharmacology Modeling and SimulationGlaxoSmithKlineResearch Triangle ParkUSA
  2. 2.Pharmacokinetics, Pharmacodynamics, Modeling and SimulationICON Development SolutionsMarlowUK

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