On Setting the First Dose in Man: Quantitating Biotherapeutic Drug‐Target Binding through Pharmacokinetic and Pharmacodynamic Models

Abstract: Although the three (perhaps four) phases of clinical drug development are well known, it is relatively unappreciated that there are similar phases in pre‐clinical development. These consist of ‘Phase I’ the initial, normally Research Discovery driven pharmacology; ‘Phase II’ non‐good laboratory practice (GLP) dose range finding, followed by pivotal ‘Phase III’ GLP toxicology. Together with an array of in vitro experiments comparing species, these stages should enable an integrated safety assessment prior to entry into man, documenting to investigators and authorities evidence that the new pharmaceutic is unlikely to cause harm. Following the lessons learned from TeGenero TGN1412 and subsequent updates to regulatory guidelines, there are aspects peculiar to biotherapeutics, especially those that target key body systems, where calculations could be made for doses for human studies using pharmacokinetic and pharmacodynamic models. Two of these are exemplified in this paper. In the first, target‐mediated drug disposition, where the binding of the drug to a cellular target quantitatively affects the pharmacokinetics, enables occupancy to be estimated without recourse to independent assays. In the second, assaying captured soluble target, as drug‐target complexes, allows estimation of the concentration of the free ligand ensuring that in initial clinical studies, soluble targets are not overly suppressed. To support this methodology, it has been demonstrated using omalizumab, free and total IgE data that such analyses do predict the suppression of the free unbound ligand with reasonable accuracy. Overall, the objective of the process is to deliver a justification, through consideration of drug‐target binding, of a safe starting and therapeutically relevant escalation doses for human studies.