Efficacy and plasma protein binding

The December issue of Nature Reviews|Drug Discovery includes an informative article from scientists at Pfizer titled ‘The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery’.  In it they discuss the ways in which plasma protein binding (PPB) data is often utilised in the lead optimisation process and, in particular, how various in vitro assays are used to predict in vivo efficacy.  They then expound on why they believe that the differences between such assays (i.e. static systems) and the in vivo situation (i.e. dynamic systems) are such that this type of practice is flawed and counter-productive.  They review the free drug hypothesis in some detail (including discussion of exceptions to the rule) and argue that the focus of drug discovery should clearly be to enhance the free drug concentration in the appropriate compartment and not to pursue PPB  as a means to such an end.  Whilst much of the ground covered in this review will not be news to many readers, it will no doubt surprise some that the authors conclude that the PPB of a drug ultimately has very little effect on in vivo efficacy.

The plasma protein binding of some of the top 100 most prescribed drugs (Click on image to enlarge)

Finally the authors also provide some guidelines for the application of PPB principles in drug discovery programmes which are summarised as follows (the article explains each point in a lot more detail):

  • Advance drug candidates based on free drug concentration
  • Avoid structural modification to reduce the free drug fraction for plasma protein binding
  • Do not use shift assays
  • Avoid the trap of total drug concentration and brain/plasma ratio
  • Discover the missing link between pharmacokinetics and pharmacodynamics

A highly recommended read covering some solid drug discovery concepts and which also provides some well considered advice for helping to identify high quality clinical candidates.

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1 Response to Efficacy and plasma protein binding

  1. Pingback: Optimization of plasma protein binding (part 2) | MedChemBuzz

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