Potency and plasma protein binding of drugs -a potentially misleading pair for predicting efficacious concentrations in humans.

In drug discovery or preclinical stages of development, potency parameters such as IC, , or have been routinely used to predict the parameters of efficacious exposure (AUC, , etc.) in humans. However, to our knowledge, the fundamental assumption that the potency is correlated with the efficacious concentration in humans has not been investigated extensively. Thus, the present review examined this assumption by comparing a wide range of published pharmacokinetic (PK) and potency data. If the drug potency and its effectiveness in humans are well correlated, the steady-state average unbound concentrations in humans [ = ·F·Dose/(·τ) = ·AUCss/τ] after treatment with approved dosage regimens should be higher than, or at least comparable to, the potency parameters assessed . We reviewed the ratios of /potency for a total of 54 drug entities (13 major therapeutic classes) using the dosage, PK, and potency reported in the published literature. For 54 drugs, the / potency ratios were < 1 for 38 (69%) and < 0.1 for 22 (34%) drugs. When the ratios were plotted against (unbound fraction), "ratio < 1" was predominant for drugs with high protein binding (90% of drugs with ≤ 5%; i.e., 28 of 31 drugs). Thus, predicting the efficacious unbound concentrations in humans using only potency data and should be avoided, especially for molecules with high protein binding.