ArticleThe AAPS journal2014
Mechanistic pharmacokinetic/target engagement/pharmacodynamic (PK/TE/PD) modeling in deciphering interplay between a monoclonal antibody and its soluble target in cynomolgus monkeys.
Article in The AAPS journal, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 46 citations in OpenAlex.
- Randomized phase I trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubart.Nature communications · 2025Trial
- Modeling and Simulation of the Pharmacokinetics and Target Engagement of an Antagonist Monoclonal Antibody to Interferon-γ-Induced Protein 10, BMS-986184, in Healthy Participants to Guide Therapeutic Dosing.Clinical pharmacology in drug development · 2020Trial
- An Innovative Multifaceted Approach to Enhance the Sensitivity of a Target Engagement ELISA.Pharmaceutical research · 2026Article
- Review
- A model-based approach using GSK3772847, an anti-interleukin-33 receptor monoclonal antibody, as a showcase to predict SC administration PK and free target dynamics based on PK and total target measurements after IV administration.CPT: pharmacometrics & systems pharmacology · 2025Article
- Siltuximab administration results in spurious IL-6 elevation in peripheral blood.American journal of hematology · 2024Article
- Best Practices in mAb and Soluble Target Assay Selection for Quantitative Modelling and Qualitative Interpretation.The AAPS journal · 2023Article
- Mathematical Modeling of Remdesivir to Treat COVID-19: Can Dosing Be Optimized?Pharmaceutics · 2021Article
- A new era for migraine: Pharmacokinetic and pharmacodynamic insights into monoclonal antibodies with a focus on galcanezumab, an anti-CGRP antibody.Cephalalgia : an international journal of headache · 2019Review
- Determination of IL-23 Pharmacokinetics by Highly Sensitive Accelerator Mass Spectrometry and Subsequent Modeling to Project IL-23 Suppression in Psoriasis Patients Treated with Anti-IL-23 Antibodies.The AAPS journal · 2019Article
- A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma.Science translational medicine · 2017Article
- Interrelationships between Infliximab and Recombinant Tumor Necrosis Factor-Drug metabolism and disposition: the biological fate of chemicals · 2017Article
- Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases.Scientific reports · 2017Article
- Minimal physiologically-based pharmacokinetic (mPBPK) model for a monoclonal antibody against interleukin-6 in mice with collagen-induced arthritis.Journal of pharmacokinetics and pharmacodynamics · 2016Article
- Deciphering the In Vivo Performance of a Monoclonal Antibody to Neutralize Its Soluble Target at the Site of Action in a Mouse Collagen-Induced Arthritis Model.Pharmaceutical research · 2016Article
- The development of therapeutic monoclonal antibodies: overview of the nonclinical safety assessment.Current pain and headache reports · 2015Review
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Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.