Using Randomization in a Clinical Study
Using One-Dimensional Arrays to Describe Collections of Numbers
Human Drug Testing Phase I: Determining the Maximum Tolerated Dose

Pharmacokinetics and Pharmacodynamics (PK/PD Studies)

As you dive deeper into the field of biostatistics, you'll need to develop a firm understanding of pharmacokinetics (PK) and pharmacodynamics (PD) and the differences between the two.

The term pharmacokinetics (PK) refers to the study of

  • How fast and how completely the drug is absorbed into the body (from the stomach and intestines if it's an oral drug)

  • How the drug becomes distributed through the various body tissues and fluids, called body compartments (blood, muscle, fatty tissue, cerebrospinal fluid, and so on)

  • To what extent (if any) the drug is metabolized (chemically modified) by enzymes produced in the liver and other organs

  • How rapidly the drug is eliminated from the body (usually via urine, feces, and other routes)

The term pharmacodynamics (PD) refers to the study of

  • The relationship between the concentration of the drug in the body and the biological and physiological effects of the drug on the body or on other organisms (bacteria, parasites, and so forth) on or in the body.

Generations of students have remembered the distinction between PK and PD by the following simple description:

  • Pharmacokinetics is the study of what the body does to the drug.

  • Pharmacodynamics is the study of what the drug does to the body.

It's common during Phase I and II testing to collect blood samples at several time points before and after dosing and analyze them to determine the plasma levels of the drug at those times. This data is the raw material on which PK and PD studies are based.

By graphing drug concentration versus time, you can get some ballpark estimates of the drug's basic PK properties: the maximum concentration the drug attains (CMax), the time at which this maximum occurs (tMax), and the area under the concentration-versus-time curve (AUC). And you may also be able to do some rudimentary PD studies from this data — examining the relationship between plasma drug concentrations and measurable physiological responses.

But at some point, you may want (or need) to do a more formal PK/PD study to get detailed, high-quality data on the concentration of the drug and any of its metabolites (molecules produced by the action of your body's enzymes on the original drug molecule) in plasma and other parts of the body over a long enough period of time for almost all the drug to be eliminated from the body.

The times at which you draw blood (and other specimens) for drug assays (the so-called sampling time points) are carefully chosen — they're closely spaced around the expected tMax for the drug and its metabolites (based on the approximate PK results from the earlier trials) and more spread out across the times when nothing of much interest is going on.

Compared to PK and PD analyses done as part of a Phase I or Phase II study, a well-designed PK/PD study yields more precise values of the basic PK parameters (CMax, tMax, and AUC) as well as more sophisticated PK parameters, such as the actual rates of absorption and elimination, information about the extent to which the drug is distributed in various body compartments, and information about the rates of creation and elimination of drug metabolites.

A PK/PD study also acquires many other measurements that indicate the drug's effects on the body, often at the same (or nearly the same) sampling time points as for the PK samples. These PD measurements include:

  • Blood and urine sampling for other chemicals that would be affected by the drug: For example, if your drug were a form of insulin, you'd want to know glucose concentrations as well as concentrations of other chemicals involved in glucose metabolism.

  • Vital signs: Blood pressure, heart rate, and perhaps rate of breathing.

  • Electrocardiographs (ECGs): Tracings of the heart's electrical activity.

  • Other physiological tests: Lung function, treadmill, and subjective assessments of mood, fatigue, and so on.

Data from PK/PD studies can be analyzed by methods ranging from the very simple (noting the time when the highest blood concentration of the drug was observed) to the incredibly complex (fitting complicated nonlinear models to the concentrations of drug and metabolites in different compartments over time to estimate reaction rate constants, volumes of distribution, and more).

blog comments powered by Disqus
How to Create a Data Dictionary to Describe Your Biostatistics Data
Thorough QT (Interval) Studies in Biostatistics
Confidence Interval Basics
The Meaning of the "p Value" from a Test
Simple and Complicated Expressions Used in Biostatistics