From Animal to Human with a new monoclonal antibody: An example of the use of pharmacokinetics only to assist on the choice of first in human dose.
Olivier Petricoul(1), Martin Spendiff(2), Andrea Kiessling(1), Simon Chivers(1)
(1) Novartis Institutes for BioMedical Research, Biologics Safety & Disposition, Basel; (2) Novartis Pharma, Modeling & Simulation, Basel
Objectives: Drug A is a fully human antibody that binds with high affinity to a ligand binding site on Cells C. Drug A is able to induce expansion of Cells C in normal young mice, young and old rats and cynomolgus monkeys. The objective of this analyze was to assist in obtaining a minimally acceptable biological effect level (MABEL) in Human.
Methods: The pre-clinical program included four studies in rats (N=2) and cynomolgus monkeys (N=2) that showed clear concentration/response relationship with Target Mediated Drug Disposition (TMDD). However, no ligand concentrations and receptor occupancy data could be obtained and thus a full mechanistic PKPD model could not be identified. Therefore, the PK profile was taken as an auxiliary biomarker that can be used for dose selection in human (assuming similar TMDD in human).
Results: The TMDD observed with rat and cynomolgus data is most likely related to a loss of target saturation below a threshold concentration. Moreover, it was shown that the PD effect took place with saturation of receptor only, i.e. in the linear portion of the PK profile. For a rapidly accessible target, saturation of clearance and target are equivalent, and the point of inflection in the exposure profiles indicating TMDD was interpreted as the point of transition between receptor saturation and first-order clearance. In humans, doses of 0.1 to 30 mg/kg were predicted to give receptor saturation rates in the range of 30 to 99.9%.
Conclusion: Preliminary results from the First in Human study confirmed the predictions from allometric scaling using PK only.