ABSTRACT

There are many reports published each year with results of the development of various pharmacometric (PM) models. These models are population (hierarchical) models that include but are not limited to pharmacokinetic, pharmacodynamic, disease progression, and outcomes link models. For population pharmacokinetic (PPK) and pharmacodynamic (PPD) models an FDA survey (1) reported that some PPK and PK/PD models developed as part of New Drug Applications (NDAs) did not add value or have any impact on the submission because the usefulness of such models was not addressed. Most PM models are developed but their applications are rarely addressed. When the purpose or intended use of the PM model is not stated, the applicability of the model is unclear. For PPK models all this continues in spite of the statement in the Guidance for Industry: Population Pharmacokinetics (The Guidance) (2), “A discussion of how the results of the analysis will be used (e.g., to support labeling, individualized dosage, safety, or to define additional studies) should be provided. In addition, the use

of graphics, often based on simulations of potential responses under the final fitted model, to communicate the application of a population model (e.g., for dosage adjustment) is recommended.” The nature of the application of a PM model must be taken into account during the entire modeling process. The intended use of a model should influence the attitude and modeling approaches used by the pharmacometrician at the various stages of the modeling process. This would determine what covariates are considered important, which parameters are of primary concern, and what are the extent and method of model evaluation and validation. Thus, it is the application or intended use of the PM model, which drives the modeling process from model development, through model evaluation, to model validation (as deemed necessary) that constitutes model appropriateness.