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# Why Should You Evaluate Dose Proportionality?

Dose proportionality is a common phrase used pharmacokinetics. Early in the pre-clinical development process, we evaluate dose proportionality in animal species. Then if the drug advances to clinical trials, one of the first assessments in humans is to evaluate dose proportionality. Why is it so important? What do we learn from understanding dose proportionality? What does it mean?

Dose proportionality occurs when increases in the administered dose are accompanied by proportional increases in a measure of exposure like AUC or Cmax. Thus an evaluation of dose proportionality usually includes exposure analysis of three or more doses to produce a graph similar to the one below:

As shown, a linear regression (or other statistical construct) is used to determine if there is a linear increase in exposure with increases in dose. In general, there are three possible outcomes:

1. Exposure is dose proportional (as shown in the figure)
2. Exposure is less than dose proportional (points would fall below the line)
3. Exposure is greater than dose proportional (points would fall above the line)

The explanation of dose proportionality does little to explain what it means. To understand the utility of dose proportionality, we need to look at the equation for clearance (see previous post):

$CL =\frac{Dose}{AUC}$ Equation 1

By rearranging this equation we get the following:

$AUC = \frac{Dose}{CL}$ Equation 2

This equation suggests that AUC is linearly related to dose. The proportionality factor is 1/CL. Thus if exposure is dose proportional, it means that clearance is constant over that same dose interval. This is the reason that it is important to test for dose proportionality.

So when testing dose proportionality for your next drug, remember that you are really testing to see if there is constant clearance.

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### 筆者について

By: Nathan Teuscher
Dr. Teuscher has been involved in clinical pharmacology and pharmacometrics work since 2002. He holds a PhD in Pharmaceutical Sciences from the University of Michigan and has held leadership roles at biotechnology companies, contract research organizations, and mid-sized pharmaceutical companies. Prior to joining Certara, Dr. Teuscher was an active consultant for companies and authored the Learn PKPD blog for many years. At Certara, Dr. Teuscher developed the software training department, led the software development of Phoenix, and now works as a pharmacometrics consultant. He specializes in developing fit-for-purpose models to support drug development efforts at all stages of clinical development. He has worked in multiple therapeutic areas including immunology, oncology, metabolic disorders, neurology, pulmonary, and more. Dr. Teuscher is passionate about helping scientists leverage data to aid in establishing the safety and efficacy of therapeutics.

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