Prospective prediction of human dose is essential for support of various early clinical development activities. These estimates determine the amount of material required for IND tox studies, provide perspective on feasibility of dosage form design, and inform estimates of exposure to allow expedient escalation into the efficacious exposure range during First In Human (FIH) trials. Dose is both a function of a candidate’s human pharmacokinetic (PK) parameters in conjunction with a target’s efficacious exposure (Is efficacy for the particular target driven by Cmax, AUC or Ctrough coverage of drug?). Several techniques exist for estimating human pharmacokinetics: allometric scaling of preclinical species PK data, estimating drug clearance using in vitro data from human liver derived systems (microsomes or hepatocytes), or simulation of a human PK profile using physiologically based pharmacokinetic (PBPK) models exclusively driven by physical chemical and in vitro ADME data. Success in estimating the human PK profile has improved significantly, and failure in the clinic due to poor pharmacokinetic properties is no longer considered a major reason for drug failure. However, arriving at an accurate dose prediction also involves some understanding of in vivo potency in preclinical models and the translation to human disease. Those targets requiring significant drug coverage for effect can result in high dose estimates even when decent PK is anticipated. Conversely, compounds showing robust efficacy at low exposure can potentially succeed with less than optimal PK. A look at the top prescribed drugs (segregated by oral products) shows the vast majority have a highest marketed dose strength &lt;100 mg. Thus, optimization of pharmacokinetics is certainly a worthwhile approach, but the influence of in vivo potency must not be overlooked as a key driver of the human dose estimate. Balancing both should provide best chance of success in clinical development.

Factors influencing the magnitude and accuracy of the projection of human dose

Macromolecular Chemistry: The Second Century

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