Pharmacokinetic analysis across studies to drive knowledge-integration: A tutorial on individual patient data meta-analysis (IPDMA).

ABSTRACT

Answering challenging questions in drug development sometimes requires pharmacokinetic (PK) data analysis across different studies, for example, to characterize PKs across diverse regions or populations, or to increase statistical power for subpopulations by combining smaller size trials. Given the growing interest in data sharing and advanced computational methods, knowledge integration based on multiple data sources is increasingly applied in the context of model-informed drug discovery and development. A powerful analysis method is the individual patient data meta-analysis (IPDMA), leveraging systematic review of databases and literature, with the most detailed data type of the individual patient, and quantitative modeling of the PK processes, including capturing heterogeneity of variance between studies. The methodology that should be used in IPDMA in the context of population PK analysis is summarized in this tutorial, highlighting areas of special attention compared to standard PK modeling, including hierarchical nested variability terms for interstudy variability, and handling between-assay differences in limits of quantification within a single analysis. This tutorial is intended for any pharmacological modeler who is interested in performing an integrated analysis of PK data across different studies in a systematic and thorough manner, to answer questions that transcend individual primary studies.