Trends of in vitro pharmacological potency and in vivo pharmacokinetics parameters of modern drugs: Can the therapeutic/subtherapeutic dose be estimated from in vitro <i>K</i>_i and pharmacokinetic parameters?

In drug discovery and development, estimating therapeutic and subtherapeutic doses is crucial for designing early-phase clinical trials, particularly first-in-human (FIH) studies. While increasing the in vitro pharmacological potency (lowering K_i) of a compound to its target is expected to decrease the therapeutic dose, its benefit is not necessarily clarified. We analyzed in vitro K_i, human in vivo pharmacokinetics (PK) parameters, and therapeutics doses of 144 oral small-molecule drugs approved in Japan (2010-2021). The data on classic drugs were obtained from Goodman and Gilman's textbook, 9th ed. (published in 1996). Modern drugs had lower K_i (2.5 nM) and daily doses (88 μmol/day) than classic drugs (33 nM and 313 μmol/day), but 3.6-fold higher intrinsic clearance (CL_int; 171 vs. 47 L/h), suggest that increasing potency over the years has not resulted in a reduction in dosage as expected. Estimating therapeutic doses using target receptor occupancy (tRO)-optimized approach improved estimation accuracy (63% within 10-fold of observed values) compared with tRO-fixed approaches. Subtherapeutic dose estimations revealed a risk of overdosing in FIH trials, indicating that these estimates are not necessarily as conservative as is generally understood. Notably, the unbound average concentration-to-K_i ratio (C_ave,u/K_i) varied among drugs and correlated negatively with K_i, suggesting the possible necessity of incorporating it into dose estimation methods. This study provides insights into the relationship between in vitro K_i, in vivo PK parameters, and therapeutic dose of modern drugs, proposing strategies and revealing the risk for dose estimation and drug development in the era of highly potent small molecules.