Profiling the estimated plasma concentrations of 215 marketed oral drugs

Abstract

The human pharmacokinetic parameters of 215 marketed oral drugs have been collated and their estimated plasma concentrations (following repeat dosing) profiled against time using a one-compartment model. The estimated ratio of maximum to minimum plasma concentration for most drugs was observed to be less than 30, and the observed human toxicity of a subset of 104 drugs showed that most displayed adverse effects at a free plasma concentration of greater than 100 nM. These two observations can be combined to form a new definition for oral drug-likeness: a drug's ratio of maximum to minimum plasma concentration should aim to be less than 30 and its maximum free plasma concentration should preferably be at most 100 nM for a therapeutic dose that is likely to be absorbed. Assessment of new compounds against this proposal can be facilitated by use of in silico ADME models and an understanding of the relevant tolerances associated to prediction errors, allowing decisions to be made on the likelihood of a compound having an optimum pharmacokinetic profile.