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Pharmacokinetics is the study of the time-course of drug and
metabolite concentrations in the body. Decades ago,
pharmacokinetic data analysis was limited to join-the-dots style
non-compartmental analysis (NCA),
which provided descriptive parameters like
Area-Under-the-Curve (AUC) or Cmax. Then, insight into the drugs behaviour would be inferred from these simply derived numbers and a
knowledge of the relevant physiology. NCA still plays a role in
bioequivalence studies and quick-and-dirty analysis, however the utility
and impact of pharmacokinetic data has increased massively since the arrival of the
population approach.
The population approach was developed by Lewis Sheiner and Stuart
Beal in the late 1970's. It's central theme is to separate the
genuine differences between individuals from the random noise in
pharmacokinetic measurements. As pharmacokinetic models are
nonlinear, this requires computer estimation of a nonlinear hierarchical model.
Fitting nonlinear hierarchical models was beyond the software of the time (and remains
challenging even today),
so Sheiner and Beal developed the NONMEM software. This innovative
package
made more advanced PKPD analysis possible. The population approach produces more
accurate estimates of physiological parameters, in particular
variability among individuals, and the final model can be used to
simulate future trials or scenarios. The population approach was a
breakthrough that was both profound and massively influential, and
perhaps even worthy of a Noble prize.
For simple datasets, the benefit of population
analysis may not be immediately obvious, compared to the relative ease
of automated non-compartmental analysis. However, as soon as datasets become
more complicated, for example with complex pharmacokinetics, multiple
studies or the addition of just a single biomarker, the population approach
is essential to fully analyze the dataset.
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