Bayesian Population Pharmacokinetic Modeling of Eltrombopag in Chronic Hepatitis C Patients
Background and Objectives
Eltrombopag is a thrombopoietic growth factor that is approved for the treatment of thrombocytopenia in chronic hepatitis C virus (HCV) patients. We aimed to describe eltrombopag population pharmacokinetics in hepatitis C patients. Bayesian statistical approach will be applied to screen for patients’ characteristics associated with eltrombopag pharmacokinetic parameters.
A population pharmacokinetic analysis was conducted using WinBUGS version 1.4.3. Data from 483 individuals with chronic HCV infection were analyzed. This analysis is a secondary analysis of two clinical studies (ENABLE1 and ENABLE2) sponsored by GlaxoSmithKline. Several patients’ characteristics were examined as possible covariates of the population pharmacokinetic model. Prior information from previous studies was incorporated in the bayesian model as prior distribution to estimate pharmacokinetic parameters.
A two-compartment pharmacokinetic model with first-order absorption with exponential error model best fit the data. We identified East Asian race and total bilirubin level as predictors of eltrombopag clearance. Typical value for distributional clearance was 0.762 L/h (95% Bayesian credible set, 0.703–0.826), for volume of distribution of the central and peripheral compartments were 12 L (10.9–13.4) and 10.9 L (10.4–11.5), and for absorption lag time was 0.947 h (0.918–0.977). Assuming an average total bilirubin of 21.7 µmol/L, the typical elimination clearance value for an East Asian patient was 0.14 L/h and for other races was 0.20 L/h.
Eltrombopag pharmacokinetic behavior was described using population bayesian approach. This model can be applied to optimize eltrombopag dosing in order to reduce the incidence of thrombocytopenia in HCV-infected patient receiving interferon-based therapy.
Compliance with Ethical Standards
No funding has been received for the conduct of this study and/or preparation of this manuscript.
Conflicts of interest
The authors declare no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 1.Abad S, Vega A, Hernandez E, Merida E, de Sequera P, Albalate M, et al. Universal sustained viral response to the combination of ombitasvir/paritaprevir/ritonavir and dasabuvir with/without ribavirin in patients on hemodialysis infected with hepatitis C virus genotypes 1 and 4. Am J Nephrol. 2017;45(3):267–72. https://doi.org/10.1159/000454819.CrossRefGoogle Scholar
- 2.Center for Disease Control and Prevention. Surveillance for viral hepatitis—United States, 2015. United States: CDC; 2015.Google Scholar
- 3.Shiffman ML. Chronic hepatitis C virus: advances in treatment, promise for the future. New York: Springer; 2011.Google Scholar
- 7.Keohane EM, Walenga JM, Smith LJ. Rodak’s hematology: clinical principles and applications. Philadelphia: Elsevier Saunders; 2015.Google Scholar
- 9.Bordin G, Ballare M, Zigrossi P, Bertoncelli MC, Paccagnino L, Baroli A, et al. A laboratory and thrombokinetic study of HCV-associated thrombocytopenia: a direct role of HCV in bone marrow exhaustion? Clin Exp Rheumatol. 1995;13(Suppl 13):S39–43.Google Scholar
- 12.Skidmore-Roth L. Mosby’s 2014 nursing drug reference. 27th ed. Mosby: Skidmore Nursing Drug Reference; 2014.Google Scholar
- 14.Hodgson BB, Kizior RJ. Saunders nursing drug handbook 2014—E-Book. Amsterdam: Elsevier Health Sciences; 2013.Google Scholar
- 17.Lexi-Comp Inc., American Pharmaceutical Association. Drug information handbook. < 1996/97 > -2008/2009: Lexi-Comp’s clinical reference library. North American ed. Hudson, Ohio Washington, DC: Lexi-Comp, American Pharmaceutical Association; 2009. p. 2117.Google Scholar
- 19.Lunn D, Jackson C, Best N, Thomas A, Spiegelhalter D. The BUGS book: a practical introduction to Bayesian analysis. Boca Raton: CRC Press; 2012.Google Scholar
- 20.Wu K, Thapar M, Farrell C, Hayes S, Guo H, Hou M, et al. Population pharmacokinetic and pharmacodynamic modeling and effects on platelet counts of different dosages of eltrombopag in chinese patients with chronic primary immune thrombocytopenia. Clin Ther. 2015;37(7):1382–95. https://doi.org/10.1016/j.clinthera.2015.03.024.CrossRefGoogle Scholar
- 22.Gibiansky E, Mudd Jr P, Kamel Y, Kamel YM, editors. Population pharmacokinetics of eltrombopag in patients with cancer and healthy subjects. AAPS Annual Meeting; 2009.Google Scholar
- 25.Ette EI, Williams PJ. Pharmacometrics: the science of quantitative pharmacology. New York: Wiley; 2013.Google Scholar
- 27.D’Argenio D. Advanced methods of pharmacokinetic and pharmacodynamic systems analysis. Berlin: Springer; 2006.Google Scholar
- 33.Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. Boca Raton: Taylor & Francis; 1982.Google Scholar
- 37.Bauer LA. Applied clinical pharmacokinetics 3/E. New York: McGraw-Hill Education; 2014.Google Scholar