title: Modeling and simulation support eltrombopag dosing in thrombocytopenic patients with chronic HCV infection.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina, 27709, USA, jianping.p.zhang@gsk.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.forename: Mita
authors.initials: M
authors.lastname: Thapar
authors.forename: Colm
authors.initials: C
authors.lastname: Farrell
authors.forename: Mary B
authors.initials: MB
authors.lastname: Wire
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001565:Benzoates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001792:Blood Platelets / Q000187:drug effects*; D016022:Case-Control Studies; D003198:Computer Simulation; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D005260:Female; D019698:Hepatitis C, Chronic / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D010976:Platelet Count; D011092:Polyethylene Glycols / Q000008:administration & dosage; D019338:Polypharmacy; D011720:Pyrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000008:administration & dosage; D013921:Thrombocytopenia / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D034061:Thrombopoiesis / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D001565:Benzoates; D006834:Hydrazines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011720:Pyrazoles; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a; C520809:eltrombopag