Impact of dose selection on parameter estimation using a rapid binding approximation model of target-mediated drug disposition



The purpose of this study was to examine the role of dose selection on population pharmacokinetic (PK) parameter estimation using a rapid binding approximation of a target-mediated drug disposition (TMDD) model previously developed for interferon-β (IFN-β). A total of 50 replicate datasets each containing 100 subjects were created using NONMEM®. The study design included IV injection of IFN-β followed by the SC route in a crossover manner, with each dose and route of administration separated by a 1,000 h washout period. Serial plasma PK samples were simulated up to 48 h for all subjects following each dose. Population mean PK parameters were re-estimated in NONMEM® for each simulated dataset using the same TMDD model after including the following doses (MIU/kg): (A) 1, 3 and 10 (original study); (B) 1, 3 and 7; (C) 1, 3 and 5; (D) 1, 3 and 4; (E) 1 and 3; (F) 3 and 10; or (G) 10 MIU/kg only. Bias in the model fit was assessed by calculating the percent prediction error (PE%) for each of the population mean PK parameters relative to the estimates obtained from the fit to the 1, 3, and 10 MIU/kg doses (Case A). Relatively unbiased population mean PK parameter estimates (median PE% <8%) were obtained only when the study design included 1, 3 and a minimum higher dose of 7 MIU/kg. Bias increased for various parameters when the highest dose was less than 7 MIU/kg along with 1 and 3 MIU/kg being the low and intermediate dose levels. An increase in the bias for binding capacity, Rtot, and the equilibrium dissociation constant, K D, was observed as the highest dose included in the dataset was reduced from 5 to 3 MIU/kg (median PE% ranged from −4.71 to −23.9% and −4.76 to −34.6%). Similar increases in the range of median PE% were also observed for other model parameters as the highest dose was reduced from 5 to 3 MIU/kg. Severely biased results were obtained from the study design that included only the 10 MIU/kg dose (Case G) suggesting that it is not sufficient to study just a high dose group. This bias was greatly reduced (median PE% <14%) for all parameters except K D when the 3 and 10 MIU/kg doses were co-modeled (Case F). Plots of the PE% for Rtot and K D versus the molar ratio of maximum dose to Rtot suggest that study designs should evaluate at least one IFN-β dose 3.5- to 4-fold higher than Rtot along with the 1 and 3 MIU/kg dose levels to obtain unbiased population PK parameter estimates. In summary, for the IFN-β model and study design, dose selection influences the ability to generate relatively unbiased population mean TMDD parameter estimates, which is based on maximum dose levels relative to Rtot. This simulation study highlights the role of dose selection in optimal study design strategies for drugs such as IFN-β that exhibit TMDD properties.


Target-mediated drug disposition Rapid binding approximation NONMEM Pharmacokinetics Simulation Interferon-β 



This research was funded, in part, by Grant GM57980 from the National Institutes of Health (D.E.M.) and a post-doctoral fellowship from Amgen, Inc. (A.M.). We wish to thank Dr. John M. Harrold at the University at Buffalo, SUNY for his computational assistance.

Supplementary material

10928_2010_9190_MOESM1_ESM.doc (286 kb)
Supplementary material 1 (DOC 286 kb)


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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Anshu Marathe
    • 1
  • Scott Van Wart
    • 1
  • Donald E. Mager
    • 1
  1. 1.Department of Pharmaceutical SciencesUniversity at Buffalo, State University of New YorkBuffaloUSA

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