A population pharmacodynamic model characterizing neutropenia associated with pegylated interferon alpha 2-a therapy in patients with chronic hepatitis C viral infection
Neutropenia is a hematologic disorder commonly reported in patients with chronic hepatitis C viral (HCV) infection. The objective of the present analysis is to describe the change in neutrophil count resulting from peglated interferon alpha 2-a (PEG-IFN α-2a) therapy in HCV-infected patients. A population pharmacodynamic model will be developed. We also plan to identify patient characteristics that contribute to the development of PEG-IFN α-2a-induced neutropenia in hepatitis C patients. A population pharmacodynamic modeling approach was applied to a cohort of patients (n = 292) with chronic HCV infection. Modeling was performed using NONMEM 6. Data was obtained from two phases III studies sponsored by Hoffmann-La Roche. Covariate screening was applied to evaluate various demographic and clinical characteristics as possible predictors of pharmacodynamic parameter during model development. A total of 4517 neutrophil counts from 292 subjects were analyzed by the proposed population pharmacodynamic model. A constant residual error model was used to the log-transformed neutrophil count. Platelet baseline count and uric acid level were identified as predictors of neutrophil pharmacodynamic model. Increased baseline platelet count is expected to result in higher neutrophil baseline. A higher neutrophil baseline is also expected in patients with increased uric acid level. In conclusion, a mechanistic pharmacodynamic model was developed. The effect of various covariates was included in the model. This allows the prediction of neutrophil count following antiviral therapy in patients with hepatitis C infection. Clinical studies: NV15942 and NV15801
KeywordsNeutropenia Hepatitis C NONMEM Pharmacodynamic Neutrophil Model
All authors approved the final version of the article, including the authorship list.
Author contribution statement
MS and NH conceived and designed research. MS developed NONMEM code and designed modeling experiment. NH analyzed data. MS and NH wrote the manuscript. All authors read and approved the manuscript.
No funding has been received for the conduct of this study and/or preparation of this manuscript.
Compliance with ethical standards
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.
Conflict of interest
The authors declare that they have no conflict of interest.
- Alter MJ, Mast EE (1994) The epidemiology of viral hepatitis in the United States. Gastroenterol Clin N Am 23:437–455Google Scholar
- Alzubiedi S, Saleh MI (2017) Predictors of severe thrombocytopenia secondary to peginterferon alfa-2a treatment in subjects with hepatitis C virus infection. Am J Ther 24(6):e670–e675Google Scholar
- Fischbach F, Fischbach FT, Dunning MB (2014) A manual of laboratory and diagnostic tests. Wolters Kluwer Health, PhiladelphiaGoogle Scholar
- Juarez-Navarro A, Vera-de-Leon L, Navarro J, Chirino-Sprung R, Diaz-Hernandez M, Casillas-Davila L, Dehesa-Violante M (2005) Incidence and severity of infections according to the development of neutropenia during combined therapy with pegylated interferon-a2a plus ribavirin in chronic hepatitis C infection. Methods Find Exp Clin Pharmacol 27:317–322CrossRefPubMedGoogle Scholar
- Saleh MI (2017) A Bayesian approach for population pharmacokinetic modeling of Pegylated interferon α-2a in hepatitis C patients. Clin Pharmacokinet 56(11):1396–1379Google Scholar
- Soto E, Staab A, Tillmann C, Trommeshauser D, Fritsch H, Munzert G, Troconiz IF (2010) Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development. Cancer Chemother Pharmacol 66:785–795CrossRefPubMedGoogle Scholar
- Wang X, Gao F, Yuan G, Shi K, Huang Y, Chen Y, Qiu R, Sun L, Liu J, Hu C, Zhou Y (2016) Ten-year follow-up analysis of chronic hepatitis C patients after getting sustained virological response to pegylated interferon-alpha and ribavirin therapy. J Viral Hepat 23(12):971–976CrossRefPubMedGoogle Scholar