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.

Interrelationships between Infliximab and Recombinant Tumor Necrosis Factor-αin Plasma Using Minimal Physiologically Based Pharmacokinetic Models

“…The interaction between cytokines and therapeutic proteins can be quantitatively characterized with PK/pharmacodynamic modeling when PK measurements of both the protein drugs and the cytokine targets are available (Wang et al, 2014;Chen et al, 2016). However, measurement of TNF-a is extremely challenging.…”

“…Several approaches are available for free ligand separation, including molecular sieving, solid-phase extraction, and affinity separations with Protein A/G resin columns (Lee et al, 2011;Wang et al, 2014). All these methods cause sample dilution, which leads to the shift of the binding equilibrium and will bias the measurement of free ligand (Lee et al, 2011).…”

Dose selection of siltuximab for multicentric Castleman’s disease

“…CRP was examined based on its correlation with serum IL-6 concentrations and association with disease severity and progression, but a In prior studies with siltuximab, total IL-6 measurements did not provide an accurate assessment of circulating bioactive IL-6 concentrations or IL-6 neutralization due to interference of siltuximab in the available IL-6 immunoassays. Mechanistic PK/TE/PD models utilizing preclinical data may be able to assist with improving our understanding of drug behavior and dose prediction for other drugs in the future [18].…”

“…Accurate quantification of IL-6 in post-siltuximab treatment samples is not currently feasible since siltuximab-neutralized antibody-IL-6 complexes distort current immunologic-based IL-6 quantification methods [18][19][20]. IL-6 is the primary factor that drives expression of CRP from hepatocytes in response to inflammatory stimuli [1,21].…”

The Development of Therapeutic Monoclonal Antibodies: Overview of the Nonclinical Safety Assessment

“…A PD marker can be a measure of receptor occupancy, ligand binding, a downstream protein target, or even a lymphocyte population that is targeted by the mAb. Correlating PK with PD provides a model to guide both nonclinical and clinical dose level selection in the evaluation of both toxicity in the nonclinical studies as well as efficacy and safety in the clinical studies [34].…”