An improved pharmacokinetics parameter to measure dose proportionality

Scientists from North America who increased the accuracy of a fundamental pharmacokinetic parameter — the area under the concentration versus time curve — have been named as the joint winners of the 2025 Journal of Pharmacy and Pharmacology (JPP) ‘Paper of the Year’ award.

Originally published on 1 March 2024, the research paper — ‘Exploring various measures of the area under the curve for the assessment of dose-proportionality and estimation of bioavailability’ — proposes that the most accurate measure of dose proportionality is obtained by calculating the area under the drug concentration versus time curve to a common fixed time value across different drug doses as opposed to the time when the last quantifiable concentration could be measured or extrapolated to infinity. Using this measure would mitigate commonly made errors in the area under the curve calculation owing to experimental limitations. 

In pharmacokinetics, the total exposure of the body to a drug is calculated by measuring the concentration of a drug in the bloodstream as a function of the time after its administration. The area under the drug concentration versus time curve from zero (time of dosing) extrapolated to infinity (AUC) is a critical metric used to estimate bioavailability, drug clearance and dose proportionality.

Calculation of the AUC requires an accurate characterisation of the linear decline portion of the drug concentration versus time curve, referred to as the ‘terminal elimination phase’ where “absorption and distribution are complete and elimination is solely responsible for loss of drug” and subsequent estimation of the terminal phase rate constant. However, experimental limitations often result in incomplete characterisation of the terminal elimination phase (particularly in lower dose studies) resulting in errors in calculating the AUC and other pharmacokinetic parameters. 

This simulation study demonstrated that the use of the AUC truncated at a fixed time is a more reliable measure to calculate dose proportionality, provided that the kinetics was linear.

Following their award, Zita Zachariah, managing editor of the Royal Pharmaceutical Society research journals, caught up with lead co-authors Brian Davies, former senior director at Janssen Pharmaceuticals and Dion Brocks, professor for the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta, Canada — who co-authored alongside Elisabeth Minhorn, former associate director at GlaxoSmithKline — to discuss the origin, fundamentals and significance of this research paper. 

Can you tell me more about what started your research on the AUC parameter?

Brian Davies (BD): AUC is a fundamental tenet in pharmacokinetics. In toxicokinetic studies, we increase drug dosage and measure the increase in its concentration in the blood; however, drug assays are not sensitive enough to measure lower concentrations of the drug (especially at lower drug dosages) leading to errors in calculation of the AUC, as well as errors while comparing the AUC calculated at lower drug doses and comparing profiles between different drug dosages. Very often it can appear that the AUC is increasing with increasing dosage but this depends on whether the kinetics are linear or non-linear. One could decide about the non-linearity depending on how much of the AUC could be measured.

I am retired but this was a problem I had been pondering on for well over a decade and decided to revisit partly as an academic exercise and partly because this is still relevant to pharmacokinetics researchers. 

Dion Brocks (DB): Missing the terminal phases is a common problem in pharmacokinetics literature. At lower dose levels, due to limitations in the assay sensitivity, the AUC values are more likely to be truncated at earlier time points when compared to higher does levels. 

Why do you think this concern hasn’t been addressed earlier?

BD: Most researchers have the AUC calculated for them by the software program analysing the pharmacokinetic data. Some users of the software may not fully appreciate the basic principles of the calculations and may overlook factors that may cause errors in the estimation of AUC.

DB: I agree. There may be a tendency on researchers to rely on the compiled numerical data outputs so much that they miss the actual data points. This is especially important for the those in the terminal phase. This in turn can lead to an underestimation of the true AUC of the drug at lower dose levels. 

What is the most important finding of this paper?

DB: That would be the use of a truncated AUC to measure dose proportionality. For example, say the lowest dose is measured until six hours after administration, In such a case, the highest dose should also be measured only until six hours after the dose. For bioavailability comparisons between formulations, the situation is more complex and we suggest the following:

“Careful consideration of the concentration versus time profile (one or multicompartment model, spacing of terminal phase concentrations from the tmax) is recommended in selecting the AUC metric.”

What are the next steps for this research?

BD: In my retirement, I have writing children’s short stories. I will leave it to the next lot of researchers like Dion to carry this forward. However, what I would hope to see is that the companies that produce the software used to measure and calculate the AUC include these results in their program.

It is important that researchers look at and interpret the actual data they are measuring instead of relying solely on the black box computer programs used to perform their calculations.

The improved calculation of the area under the curve parameter will have implications for pharmacokinetics and drug development researchers and is also a stark reminder to researchers to look at actual data points in their calculations instead of solely relying on computer programs.