The identified helium-cooled lead-lithium and pebble-bed breeder blankets accidents analyses uncertainties and results obtained in their assessment both in models qualifications and applications to three selected accident scenarios are reported.
In the model qualification step, simulated P1NP and CTX were consistent with changes in the turnover markers from three clinical trials with romosozumab and two clinical trials with blosozumab (Supplementary Figure 3).
The FDA reviewers' recommendation, based on their independent model qualification using phase I data and subsequent simulations representative of the registration trial, was that "the dose regimen should be further optimized to address the safety concerns for hypercalciuria".
For plasma PK profiles and urinary metabolite ratios, model qualification was performed by comparing population mean or individual values of the observations with the model predictions.
CoSMoS, the principled design framework used in the development of ARTIMMUS, for example, shares many key features with the methods for physiological model qualification in drug discovery proposed by Friedrich and Savic.
Model qualification was conducted using standard nonparametric bootstrap (n = 1,000) and visual predictive check to evaluate the precision of model parameter estimates and robustness of the final PK and efficacy models.
In the recently proposed framework for model qualification of physiological models, the first step frames the project questions and the project team agrees on the use of the model inferences for the decision making.
The three main companies providing PBPK software used in clinical pharmacology regulatory submissions to date (GastroPlus, PK-Sim, and SimCYP) provided short summaries of their approach to system model qualification.
Model qualification showed: 1) good agreement between the individual, clinically measured values for SLD and those predicted by the model; 2) acceptable uncertainty in parameter values, as measured by the standard error (Table 2); 3) good agreement with actual patient observations in a simulation of two sets of 10,000 virtual patients.
