Abstract
Recent years, pharmacometric modeling and simulation (M&S) techniques have a key role at every stage of global clinical drug development, and the population pharmacokinetic (PPK) /exposure-response (ER) modeling and analysis outputs are also mostly involved in regulatory documents to be submitted during and post Japan NDA filing. In this paper, theoretical backgrounds in ER modeling are outlined to describe PK-exposures/clinical outcomes causal relationship in clinical database from randomized dose controlled trials (RDCT), considering how to handle confounding factors on causal relationship of PK-exposures/Clinical responses. Next, there are two important application examples, where ①GEE modeling approaches for time to variant exposure/efficacy variables and ②M&S extrapolation to pediatrics from adults are outlined. The GEE model provided reliable assessments on recommended dose selection and optimize study plan on the clinical endpoint. By the 2nd PPK/PD M&S, the pediatric clinical study was enabled to maximize Benefit-Risk ratios in target pediatric patients’ population. These typical PPK/ER approaches could provide highly informative outputs not only for clinical drug development, but also regulatory decision making. Furthermore, some additional consideration are forecasted in conclusion such as copula regression, chronological hierarchical bayes model, and biomarker covariates to manage more complicated clinical study design.
