Progress towards prediction of human pharmacokinetic parameters from in vitro technologies.
This review provides an academic view of the current status on using in vitro systems for the prediction of human in vivo drug clearance and inhibition interaction potential. It stresses that although in vitro technology continues to develop in an impressive way and expectations are high within the pharmaceutical industry, the potential of prediction process is yet to be fully realized. The principles of scaling and modeling in vitro parameters have a sound base and have been validated by using animal tissue. However, it is clear that the comparatively simple standard approach developed and validated in animal systems, results in a high incidence of underprediction for parameters describing clearance and inhibition interaction potential when applied to humans. There are several challenges to our ability to interpret the human in vitro data that can now be so readily generated, in particular, accommodating the unusual kinetic properties characteristic of CYP3A4 substrates, namely, positive and negative cooperativity, in the assessment of inhibition potential.
Houston
J Brian
JB
University of Manchester, School of Pharmacy & Pharmaceutical Sciences, Manchester, UK. Brian.Houston@man.ac.uk
Galetin
Aleksandra
A
D006801:Humans; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011237:Predictive Value of Tests; D013678:Technology, Pharmaceutical / Q000379:methods / Q000639:trends*
D004364:Pharmaceutical Preparations