Introduction: The ultimate objective of optimizing adsorption, distribution, metabolism and excretion (ADME) parameters in drug discovery is to maximize the unbound concentration at the site of action for a given dose level. This has the added benefit of minimizing the efficacious dose, reducing the potential for attrition related to drug burden and direct organ toxicity. The concept of drug efficiency was formulated as a tool to obtain a balanced profile between target affinity and ADME properties during lead optimization.
Areas covered: The authors discuss how it is possible to maximize the in vivo pharmacological potential addressing whether drug efficiency adds value to the decision-making process and whether it is possible to introduce a single optimization parameter, the drug efficiency index (DEI), linking target affinity and ADME properties, as a marker of in vivo efficacy.
Expert opinion: In the absence of a clear hypothesis-driven approach at the beginning of the program (i.e., pharmacokinetic-pharmacodynamic link), the objective to select molecules with a low therapeutic dose is still a major hurdle in drug discovery. The authors believe that a greater strategic focus on mechanistically relevant measures of the determinants of receptor occupancy would help the optimization and selection process. In this respect, the introduction of the DEI, which can be seen as a correction of target affinity by the in vivo pharmacokinetic potential, may help drug discovery to select and promote those molecules with the highest probability to interact with the biological target and with the best balance between target affinity and ADME properties.