Implementing population modeling, commonly called Pop PK/PD, for your pharmacokinetic (PK) or pharmacokinetic/pharmacodynamics (PK/PD) analysis is an essential tool of the drug development process and, in some demographics (like infants), a necessity.
What is Pop PK/PD?
Population modeling provides estimates of typical drug levels and drug effects (PK or PK/PD parameters) in a specific population by identifying sources of variability (covariates) in a population and then quantifying the impact of each covariate through a modeling system.
Population PK or PK/PD modeling uses the statistical methodology, nonlinear mixed effects modelling (NONMEM), to:
- Investigate PK or PK/PD variability
- Identify significant intrinsic and/or extrinsic factors (covariates) affecting pharmacokinetic or pharmacodynamics and
- Define dose-concentration-effect relationships
- Because population modeling can estimate typical PK or PK/PD parameters for a specific population, it allows study directors to forecast and model how a drug might interact with other factors before clinical trials begin.
Why is Pop PK/PD necessary?
One significant way that PK and PK/PD modeling is used is to help refine the correct dosage. For example, a subject’s demographic, genetic, pathophysiologic and therapeutic features, such as body weight, excretory and metabolic functions and the presence of other therapies can regularly alter the dose-concentration-effect relationship.
In drugs that are mainly eliminated via urinary excretion, the steady-state concentrations are usually greater in subjects with renal dysfunction compared to those in subjects with normal renal function. Population analysis identifies and quantitates this difference, assesses whether this difference will alter the dose-concentration-effect relationship, and then consequently determines if dose adjustment is needed—all before clinical trials begin.
Note: a dosing regimen based on Pop PK or PK/PD analysis should be included in the drug label.
How does Pop PK/PD modeling work? (1)
We run hundreds of PK modeling simulations every year; here’s the process we typically follow:
When should you use Pop PK modeling?
Traditional PK analysis (sometimes called individual PK analysis) can be useful when you don’t have a lot of time to run a more comprehensive population PK; however, if you have the time and access to big data, running a population PK will give you significant simulations and predictions and allow you to understand how individuals from different populations may respond differently to your drug compound.
Comparison: Traditional versus Pop PK Approaches
Key Areas: Population PK/PD Modeling is Particularly Effective for Pediatric Clinical Pharmacology
The efficacy and safety of drugs for premature infants and newborns are largely unknown and empirical with frequent under and overdosing problems due to the difficulty in obtaining sample collections from this demographic. Population PK or PK/PD modeling analysis, however, can be applied to sparse and unbalanced data sets obtained from a pediatric population in order to identify a safe and effective dosing regimen for each unique age group. Today, population PK or PK/PD modeling is highly recommended as the primary analysis method for determining the appropriate dose/regime selection in pediatric drug development.
Population PK Data Analysis Workshop by Jill Fiedler-Kelly, University of Buffalo, Buffalo, NY, 2015.