Population pharmacokinetic model of pegylated interferon alfa-2a in healthy Korean male subjects

Aims: Pegylated interferon alfa-2a is an antiviral drug approved for the treatment of chronic hepatitic B and C. The addition of polyethylene glycol (pegylation) enhances the half-life of the interferon relative the native form. Two population pharmacokinetic models1),2) of pegylated interferon alfa-2a have been published so far.  To our knowledge, no population pharmacokinetic model has been built using Korean subjects. Our study aims to develop a population pharmacokinetic model of pegylated interferon alfa-2a in healthy Korean male subjects and compare the final model and estimated parameters with those reported in the literature.

Methods: PK data were acquired from a previous clinical trial study where a single dose of 180ug of pegylated interferon alfa-2a was subcutaneously injected. The total number of subjects who participated in the study was 34. 4 subjects were excluded from our analysis because their plasma concentrations were all below the limit of quantification. Baseline concentration was estimated as a model parameter since 8 subjects had non-zero baseline plasma concentrations. Theory-based allometry was assumed in incorporating weight into volume and clearance. Model building was carried out using NONMEM ver 7.3. R version 3.2.1 was used for data exploration and analysis.

Results: One compartment model with 1st order absorption was chosen for the basic structural model. Proportional error was assumed for residual variance. Mixture model assuming two subpopulations was applied to bioavailability (F). Bioavailability value was fixed to 0.83) in the first subpopulation based on previous reports. F of the second subpopulation was estimated to be 0.108. The estimated mixture proportions were 62.3% and 47.7%. The estimates of volume, clearance, absorption rate constant, baseline concentration were 9.034 L, 0.091 ,  0.015  and 293.6 , respectively. The CV(%) of proportional residual error () was estimated to be 42%. The model described the time course of observed concentrations quite well.

Conclusion: We successfully built a population PK model of pegylated interferon alfa-2a in Korean healthy male subjects. Our model classified two subpopulations with widely differing bioavailability.Further studies would be needed to elucidate the physiological underpinnings of such differences. Genetic differences in drug absorption or disposition will be sought.

References

  1. Tomohisa SAITO, Satofumi IIDA and takehiko Kawanishi: Population Pharmacokinetic-Pharmacodynamic Modeling and Simulation of Platelet Decrease induced by Peg-interferon-alpha 2a

  2. Mari SHIOMI and Tomoo FUNAKI: Pharmacokinetic/Pharmacodynamic Model analysis of Pegylated Interferon alpha-2a in healthy subjects: Jpn J Clin Pharmacol Ther 34(4) July 2003 Page 177~185                

  3. PEG-IFN general PK and PD.pdf Page 9