title: Mechanistic pharmacokinetic/target engagement/pharmacodynamic (PK/TE/PD) modeling in deciphering interplay between a monoclonal antibody and its soluble target in cynomolgus monkeys.
abstract: 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.
authors.affiliation: Biologics Clinical Pharmacology, Janssen R&D, Spring House, Pennsylvania, USA.
authors.forename: Weirong
authors.initials: W
authors.lastname: Wang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
authors.forename: Rajitha
authors.initials: R
authors.lastname: Doddareddy
authors.forename: Damien
authors.initials: D
authors.lastname: Fink
authors.forename: Thomas
authors.initials: T
authors.lastname: McIntosh
authors.forename: Hugh M
authors.initials: HM
authors.lastname: Davis
authors.forename: Honghui
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D002097:C-Reactive Protein / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D008954:Models, Biological; D008956:Models, Chemical; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D002097:C-Reactive Protein; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors; C504234:siltuximab