P. Milligan(1) , M. Karlsson(2) , D. Nichols(1)
Early Clinical Research Group, Pfizer Central Research,
Sandwich, Kent. CT13 9NJ United Kingdom(1)
Division of Biopharmaceutics and Pharmacokinetics, University
of Uppsala. S-75123 Uppsala. Sweden(2)
During the drug development process compounds that exhibit large (unexplained) interindividual differences in plasma concentrations may fail to be advanced as a result of unpredictable efficacy and/or side effect profiles. The population approach has been shown to be a means of identifying and quantifying the factors that may produce pharmacokinetic and/or pharmacodynamic variabilities (interindividual and intraindividual). Consequently adoption of this approach at an early stage (Phase I/II) of the development process could confer a number of advantages:
a) Elucidation of the structural pharmacokinetic model will allow sources of pharmacokinetic variability e.g. non-linearity with respect to dose, concentration, time; formulation effects, and if appropriate, genetic polymorphic status and metabolite influences etc. to be identified.
b) The model can then be applied (and refined) to patient data (probably of most interest to developers) leading to identification of the pathophysiological factors that can significantly influence the disposition of the compound.
c) Provided that an ''acceptable level'' of variability has been explained, as a result of a) and b) the decision to progress the candidate into Phase III can then be facilitated with dosage recommendations (initiating and adjustments) for future studies. Additionally, as a consequence of these analyses there may be indications that certain special subgroup studies e.g. drug-drug interaction, elderly-young comparisons, may not even be necessary.
The application of this scheme will be illustrated with a compound under development at Pfizer which exhibits a number of the pharmacokinetic characteristics detailed above.