Impact of dose selection on parameter estimation using a rapid binding approximation model of XXXX .

@entity72028 @entity734 @entity2391
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 @entity734 ( @entity734 ) model previously developed for @entity2391 ( @entity2391 ). A total of 50 replicate datasets each containing 100 subjects were created using NONMEM. The study design included IV injection of @entity2391 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 @entity734 model after including the following doses (MIU/kg): (A) 1, 3 and 10 (original study); @entity72028 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 @entity2391 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 @entity2391 model and study design, dose selection influences the ability to generate relatively unbiased population mean @entity734 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 @entity2391 that exhibit @entity734 properties.
