Mechanistic Pharmacokinetic/Target Engagement/Pharmacodynamic (PK/TE/PD) Modeling in Deciphering Interplay Between a Monoclonal Antibody and Its Soluble Target in Cynomolgus Monkeys
Tóm tắt
For therapeutic monoclonal antibodies (mAbs) against soluble ligands, the free ligand level can, theoretically, be used as a surrogate for efficacy. However, it can be extremely challenging technically to measure free ligand level in the presence of an excessive amount of antibody–ligand complex. The interplay among such mAbs, ligands, and the downstream pharmacodynamic (PD) effects has not been well defined. Using siltuximab and interleukin-6 (IL-6) as model compounds, a pharmacokinetic (PK)/target engagement (TE) model was established via simultaneous fitting of total siltuximab, total IL-6, and free IL-6 concentration profiles following a low dose of siltuximab in cynomolgus monkeys. The model adequately captured the observed data and provided estimation of model parameters with good precision. The PK/TE model was used to predict free IL-6 profiles at higher siltuximab doses, where the accurate determination of free IL-6 concentration became technically too difficult. The measured free IL-6 levels from the low-dose groups and PK/TE model-predicted free IL-6 levels from the high-dose groups were used to drive an indirect response TE/PD model to describe the concentration–effect relationship between free IL-6 and C-reactive protein (CRP). The TE/PD model adequately captured both CRP elevation and CRP suppression in response to free IL-6 concentration change from baseline with a linear stimulation function, providing direct evidence that the PK/TE model-predicted free IL-6 levels from the high-dose groups were accurate. Overall, the results provided an integrated PK/TE/PD modeling and bioanalytical framework for prediction of efficacious dose levels and duration of action for mAbs against soluble ligands with rapid turnover.
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