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-beta (IFN-beta). A total of 50 replicate datasets each containing 100 subjects were created using NONMEMA (R). The study design included IV injection of IFN-beta 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 NONMEMA (R) 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, R-tot, 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 R-tot and K (D) versus the molar ratio of maximum dose to R-tot suggest that study designs should evaluate at least one IFN-beta dose 3.5- to 4-fold higher than R-tot along with the 1 and 3 MIU/kg dose levels to obtain unbiased population PK parameter estimates. In summary, for the IFN-beta 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 R-tot. This simulation study highlights the role of dose selection in optimal study design strategies for drugs such as IFN-beta that exhibit TMDD properties.