Application of Physiologically Based Pharmacokinetic (PBPK) Modeling to Support Dose Selection: Report of an FDA Public Workshop on PBPK

Abstract

The US Food and Drug Administration (FDA) public workshop, entitled “Application of Physiologically-based Pharmacokinetic (PBPK) Modeling to Support Dose Selection focused on the role of PBPK in drug development and regulation. Representatives from industry, academia, and regulatory agencies discussed the issues within plenary and panel discussions. This report summarizes the discussions and provides current perspectives on the application of PBPK in different areas, including its utility, predictive performance, and reporting for regulatory submissions.

Impact of Physiologically Based Pharmacokinetic Models on Regulatory Reviews and Product Labels: Frequent Utilization in the Field of Oncology

“…In the majority of cases, PBPK models were used for the prediction of the effect of metabolic enzyme mediated drug‐drug interactions (DDIs; Figure 1a; Tables 1–4). Importantly, the frequency of model use is consistent with the perceived level of reliability 1, 3, 5…”

“…In particular, the extrapolation of the effect of strong inhibitors or inducers to less potent perpetrators constituted the majority of the applications (11 among 13 NMEs; Table 1, IDs 1–11), and all applications resulted in labeling recommendations ( Table 1). In these cases, existing clinical data with strong perpetrator(s) were used to “anchor” the PBPK model performance, namely by accurately providing fraction metabolized by a particular enzyme, which provides a higher level of confidence in DDI prediction 1, 5. For example, a fourfold dose reduction of ibrutinib was recommended for patients taking moderate cytochrome P450 (CYP)3A inhibitors based on the PBPK model validated with clinical DDI data using strong perpetrators.…”

“…Other PBPK applications observed in the NDA review documents include prediction of the effect of hepatic impairment (HI; Table 4), but PMRs were issued for three of four NMEs to conduct or complete dedicated clinical studies, presumably because of the low level of reliability 1. In the case of obeticholic acid, the effect of HI on hepatic exposure was explored with PBPK simulations, and this helped to inform the dosing recommendation in patients with HI.…”

“…One salient feature is that PBPK models allow for the mechanistic and prospective prediction of a drug's pharmacokinetic profiles and aids in new drug development and regulatory decision‐making process 1, 2, 3, 4, 5. We surveyed the utilization of PBPK in the US Food and Drug Administration (FDA) approval, specifically focusing on their application and impact on labeling recommendations.…”

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

“…Validated mechanistic models have the advantage in their ability to predict the impact of pathophysiological changes, such as those encountered in chronic kidney disease, or in population sub-groups that have not been investigated in clinical studies. As a high proportion of drugs (>40%) approved in 2013 and 2014 did not have dose recommendations for severe renal impairment (4), mechanistic models may guide the design of clinical studies and dose recommendations (5).…”