USA – Supporting Drug Development Through Physiologically Based Pharmacokinetic Modeling

CDER clinical pharmacologists are helping the drug development community use computational models to achieve safe and effective dosing recommendations for patients who are taking more than one drug.

The 16th-century Swiss physician and philosopher Paracelsus once said, “All things are poison, and nothing is without poison. The dosage makes it either a poison or a remedy.” This quote underscores the fact that developing the right dosing recommendations for a drug is a critical step in preventing drug toxicities while ensuring effectiveness. These recommendations depend on knowledge of a drug’s pharmacokinetics—the time course of its absorption, distribution, metabolism, and excretion—and its pharmacodynamics—the relationship between drug concentration at the site of action and the resulting effect. The pharmacokinetics and pharmacodynamics of a new drug are studied in clinical trials, and it is the evidence from these trials that forms the basis for determining its correct dosing.

However, many factors may influence a drug’s pharmacokinetics, making it difficult or impossible to provide direct evidence for its safe and effective use in all patients. These factors include age, sex, the presence of various comorbidities and organ dysfunctions, and other drugs a patient may be using. Trying to address all of these factors in clinical studies would require huge, expensive trials and could severely impede drug development.

Mathematical models called physiologically based pharmacokinetic (PBPK) models make it possible to simulate clinical trials that support dosing recommendations, as well as improve the design of real trials. This effort, which is a major focus of CDER research, has recently resulted in significant benefits to the drug development community…