Modeling and simulation support eltrombopag dosing in thrombocytopenic patients with chronic HCV infection.

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.

• Authors: Jianping Zhang, Mita Thapar, Colm Farrell, Mary B Wire
• Journal: Pharmaceutical research (Pharm Res) Vol. 32 Issue 6 Pg. 2015-28 (Jun 2015) ISSN: 1573-904X [Electronic] United States
• PMID: 25534682 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Benzoates
• Hydrazines
• Interferon alpha-2
• Interferon-alpha
• Pyrazoles
• Recombinant Proteins
• Polyethylene Glycols
• peginterferon alfa-2b
• peginterferon alfa-2a
• eltrombopag

Topics

• Adult
• Aged
• Antiviral Agents (administration & dosage, adverse effects)
• Benzoates (administration & dosage, pharmacokinetics)
• Blood Platelets (drug effects)
• Case-Control Studies
• Computer Simulation
• Drug Administration Schedule
• Drug Dosage Calculations
• Drug Interactions
• Female
• Hepatitis C, Chronic (blood, complications, diagnosis, drug therapy)
• Humans
• Hydrazines (administration & dosage, pharmacokinetics)
• Interferon alpha-2
• Interferon-alpha (administration & dosage)
• Linear Models
• Male
• Metabolic Clearance Rate
• Middle Aged
• Models, Biological
• Platelet Count
• Polyethylene Glycols (administration & dosage)
• Polypharmacy
• Pyrazoles (administration & dosage, pharmacokinetics)
• Recombinant Proteins (administration & dosage)
• Thrombocytopenia (blood, diagnosis, drug therapy, etiology)
• Thrombopoiesis (drug effects)
• Young Adult