A population pharmacodynamic model characterizing neutropenia
associated with pegylated interferon alpha 2-a therapy in patients
with chronic hepatitis C viral infection
Mohammad I. Saleh
Nagham N. Hindi
Received: 1 December 2017 /Accepted: 22 May 2018
Springer-Verlag GmbH Germany, part of Springer Nature 2018
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 pharma-
codynamic 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
Globally, chronic hepatitis C virus (HCV) infection has an
estimated prevalence of 2.35% in 2011 (160 million chroni-
cally infected individuals) (Lavanchy 2011). Untreated chron-
ic hepatitis C can cause long-term complications. These in-
clude cirrhosis, end-stage liver disease, and hepatocellular car-
cinoma (Alter and Mast 1994).
Pegylated interferon alpha 2-a (PEG-IFN α-2a) is an ap-
proved antiviral for the treatment of chronic HCV infection.
PEG-IFN α-2a therapy can help acheive a sustained viral
response (SVR). Attaining a SVR improves long-term im-
provement in disease progression (Wang et al. 2016), and
probably, reduces the likelihood of developing cirrhosis and
liver cancer (Camma et al. 2001).
Chronic HCV-infected patients have a tendency to de-
velop cytopenia, particularly neutropenia (Sheehan et al.
2013). Neutropenia is a side effect of interferon-based
therapy. Neutropenia can also occur in hepatitis C pa-
tients that did not receive interferon-based therapy. This
attributed to other reasons including hypersplenism and
autoimmune reactions (Sheehan et al. 2014). Pegylated or
non-pegylated interferon (IFN) with or without ribavirin
combinations is commonly associated with hematological
adverse effects. Neutropenia occurs in approximately
45% of hepatitis C patients (Juarez-Navarro et al.
2005). Pegylated interferons have a higher incidence rate
of neutropenia compared to non-pegylated interferons
(Fried et al. 2002).
* Mohammad I. Saleh
Nagham N. Hindi
School of Pharmacy, The University of Jordan, Amman 11942,
Naunyn-Schmiedeberg's Archives of Pharmacology