How drug-like are ‘ugly’ drugs: do drug-likeness metrics predict ADME behaviour in humans?

• The QED drug-likeness score can predict some drug ADME parameters in humans.
• High QED drugs exhibit higher absorption and bioavailability than low QED drugs.
• High QED drugs have fewer drug–drug interactions and P-glycoprotein effects.
• High and low QED drugs exhibit the same distribution and elimination behaviour.
• High and low QED drugs have similar free fractions in plasma.

Using a published drug-likeness score based on the calculated physicochemical properties of marketed oral drugs (quantitative estimate of drug-likeness, QED) and published human data, high-scoring and low-scoring drugs were compared to determine how well the score correlated with their actual pharmaceutical and pharmacokinetic (PK) profiles in humans. Drugs with high QED scores exhibit higher absorption and bioavailability, are administered at lower doses and have fewer drug–drug interaction warnings, P-glycoprotein interactions and absorption issues due to a food effect. By contrast, the high-scoring drugs exhibit similar behaviour to low-scoring drugs with respect to free fraction in plasma, extent of gut-wall metabolism, first-pass hepatic extraction, elimination half-life, clearance, volume of distribution and frequency of dosing.