Scientific Publications by FDA Staff

J Clin Pharmacol 2015 Oct;55(10):1073-8

A proposal for scientific framework enabling specific population drug dosing recommendations.

Jadhav PR, Cook J, Sinha V, Zhao P, Rostami-Hodjegan A, Sahasrabudhe V, Stockbridge N, Powell JR

Over the last three decades, there has been little to no change in the paradigm to derive dosing recommendations in specific populations (e.g., hepatic or renal failure, elderly, obesity, pregnancy, ethnicity, burn patients) despite better understanding of clearance pathways in these groups and availability of modeling and simulation tools to inform dosing. A survey of current labels found that dosing recommendations for specific populations are often not available at the time of drug approval or they may be incomplete. Currently there is no regulatory framework to incorporate model-based specific population dosing recommendation based on model-based predictions. The purpose of this paper is to propose a scientific framework for using modeling and simulation to support specific population dosing i.e. getting the dose right in specific populations. We are proposing a framework that creates a knowledgebase of drug and population attributes where model-based approach can be used to inform dosing recommendations. We envision two broad implications of this framework- * Informing inclusion of specific populations in pivotal studies * Providing dosing guidelines for specific populations when availability of pharmacokinetic data might be difficult (e.g. pregnancy) or impossible (e.g. drugs developed for rare diseases or complex scenarios involving multiple comorbidities) at the time of approval. The paper discusses a research approach to determine specific population dose prediction along with challenges and risks. We hope to initiate this dialogue to explore the role of physiologic or empirical modeling methods based on prior data for drugs with similar clearance mechanisms to predict drug dosing. Through this initiative, using renal and hepatic impairment populations as prototypes, we are proposing a framework to establish rational dosing at the time of approval, streamline clinical pharmacology studies in specific populations and improve patient care particularly for groups who are underserved due to practical limitations to generate empirical data (pregnancy, burn patients etc. or rare disease conditions).