J Pharm Sci. 2018 Sep 1. pii: S0022-3549(18)30518-5. doi: 10.1016/j.xphs.2018.08.017. [Epub ahead of print]
Population PK-PD model of pegylated interferon alfa-2a in healthy Korean men.
Jung YS1, Chae D1, Park K2.
Author information
1
Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea.
2
Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea. Electronic address: [email protected].
Abstract
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 α-2a in a Korean population. For PK, IFN alfa-2a concentrations were described by a one compartment model with first order absorption, preceded by skin-to-depot first order input. For PD, serum 2'-5' oligoadenylsynthetase (2'-5' OAS) activity was described by an effect compartment model incorporating a tolerance compartment. The baseline serum 2'-5' OAS 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 > 250pmol/dl. Our results can serve as a basis for improving dosing regimens of PEG-IFN α-2a in adult patients with chronic hepatitis B or C infection.
KEYWORDS:
2’-5’ OAS; Allometry; Interferon; NONMEM; Pegylation; Population PK-PD; Tolerance