To understand population PK, first you have to understand pharmacokinetics (PK) and pharmacodynamics (PD). To provide a brief overview, PK is the study of what the body does to a drug and PD is the study of what the drug does to the body (effect of drug exposure). PK is also understanding a drug’s ADME characteristics (absorption, distribution, metabolism, and elimination).
PK/PD and Population PK/PD is an important component of every drug development program. In this post we will answer some common questions about population PK.
What is Population PK?
Population PK (popPK) is the study of variability in drug concentrations among individuals in the target patient population receiving clinically relevant doses of a drug of interest. Population PK involves collecting few or sparse PK samples (e.g., plasma drug concentration) from many patients in clinical studies (i.e., the population). In comparison, clinical pharmacology or healthy volunteer studies typically collect dense or rich PK samples from small numbers of subjects. PopPK uses mathematical models to describe the data and conduct popPK analyses.
Why conduct a Population PK analysis?
- To gain insight into drug characteristics across the patient population
- To support marketing authorization applications (NDA, BLA, etc.)
- To design better clinical studies and provide information for strategic drug development decisions
- To obtain integrated information on pharmacokinetics, not only from sparse data obtained from patients with a target disease. (Note that relatively dense/rich data or a combination of sparse and dense/rich data can also be used in population PK analysis)
- To perform the analysis of data from a variety of clinical studies, such as from pediatric and elderly patients or data obtained during the evaluation of the dose-response and exposure-response relationships (i.e., comparison between dose or concentration and efficacy or safety).
Is Population PK necessary?
Yes! A survey of 206 new drug applications and supplements reviewed by the Office of Clinical Pharmacology and Biopharmaceutics of the FDA in fiscal years 1995 and 1996 showed that almost one-quarter (i.e., 47) of the submissions contained pop PK and/or pharmacodynamic reports. Because of early integration of pop PK studies with clinical studies, the pop PK approach provided useful safety, efficacy, and dosage optimization information for the drug label in 83 percent of the 47 submissions. In the other 17 percent of the 47 applications, the pop PK approach provided results that were in agreement with previous pharmacokinetic findings although it did not yield modifications in labeling.
What can I learn from Population PK modeling?
In contrast to traditional pharmacokinetic (PK) evaluation, the population PK approach encompasses some or all of the following features:
- Understanding relevant pharmacokinetic information in patients who are representative of the target population to be treated with the drug.
- The identification and measurement of variability during drug development and evaluation.
- The explanation of variability by identifying factors of demographic, pathophysiological, environmental, or concomitant drug-related origin that may influence the pharmacokinetic behavior of a drug.
- The quantitative estimation of the magnitude of the unexplained variability in the patient population.
All of these components are needed during the FDA’s evaluation of a drug for marketing authorization (NDA or BLA).
Is understanding variability important?
The magnitude of the unexplained (random) variability is important because the efficacy and safety of a drug may decrease as unexplainable variability increases. Defining the optimum dosing strategy for a population, subgroup, or individual patient requires resolution of the variability issues.
How important is Population PK?
A population PK model should be developed with pharmacodynamic purpose in mind. A pharmacokinetics / pharmacodynamics (PK/PD) analysis of a drug in the drug development process; relating drug’s dose (or a measure of exposure) to drug’s response in a target population is always at the heart of any determination of the safety and effectiveness of drugs. Modeling and simulation is especially crucial when the clinical data is sparse such as in the cases of pediatrics or orphan (rare) diseases.