Pegylated interferon alfa-2a (PEG-IFN alfa-2a), which was developed to overcome the disadvantages of conventional formulations, is widely prescribed for hepatitis B or C virus infection. It is characterized by pharmacokinetic (PK) and pharmacodynamic (PD) properties much different from those of conventional forms. The present study developed a population PK-PD model of subcutaneous PEG-IFN alfa-2a in a Korean population. For PK, IFN alfa-2a concentrations were described by a 1-compartment model with first-order absorption, preceded by skin-to-depot first-order input. For PD, serum 2'-5' oligoadenylsynthetase activity was described by an effect compartment model incorporating a tolerance compartment. The baseline serum 2'-5' oligoadenylsynthetase level was found to have an inverse relationship with sensitivity to tolerance, leading to high tolerance at low baseline. The model revealed that subjects with low baselines experienced time delay, while those with high baselines showed tolerance in their concentration-effect relationships. The developed models matched well with data and simulation results, and the model showed that the optimal dose decreases with the baseline, with no dose effective for a baseline >250 pmol/dL. Our results can serve as a basis for improving dosing regimens of PEG-IFN alfa-2a in adult patients with chronic hepatitis B or C infection.
Keywords: 2’-5’ OAS; NONMEM; allometry; interferon; pegylation; population PK-PD; tolerance.
Copyright © 2018. Published by Elsevier Inc.