Pharmacokinetic‐pharmacodynamic modelling of the anti‐FcRn monoclonal antibody rozanolixizumab: Translation from preclinical stages to the clinic
Open accessAbstract
Rozanolixizumab is a fully humanized high‐affinity anti‐human neonatal Fc receptor (FcRn) monoclonal antibody (mAb) that accelerates the removal of circulating immunoglobulin G (IgG), including pathogenic IgG autoantibodies, via the natural lysosomal degradation pathway. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model characterizing the effect of rozanolixizumab on IgG levels in cynomolgus monkeys, translate it into humans to support the first‐in‐human (FIH) rozanolixizumab clinical trial study design, and, ultimately, develop a PK/PD model in humans. Simulations from the preclinical model were performed to predict IgG responses in humans and select clinically relevant doses in the FIH study. Good alignment was observed between predicted and observed reductions in IgG, which increased with increasing dose in the FIH study. The model successfully described the PK of the 4 and 7 mg/kg intravenous (i.v.) dose groups, although the PKs were underpredicted for the 1 mg/kg i.v. dose group. Updating the model with subsequent human data identified parameters that deviated from preclinical assumptions. The updated PK/PD model was able to effectively characterize the PK FcRn‐IgG nonlinear system in response to rozanolixizumab in the FIH data.
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The high affinity of rozanolixizumab for FcRn at neutral and acidic pH, coupled with the large sink of FcRn in the circulation, leads to target-mediated drug disposition (TMDD), which translates as non-linear pharmacokinetics.
“The high affinity of rozanolixizumab for FcRn at neutral and acidic pH, coupled with the large 'sink' of FcRn in the circulation, leads to target-mediated drug disposition (TMDD), which translates as non-linear pharmacokinetics (PK).”
From The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro (2026) · cites this paper as [41]
The Introduction reports nonlinear rozanolixizumab pharmacokinetics indicative of TMDD, and the Discussion reports high FcRn affinity at both neutral and acidic pH. The Methods place FcRn near the blood compartment because it is highly expressed on vascular endothelial cells, but describe this as a modelling assumption; they do not establish a large FcRn sink in the circulation itself. Page numbers are unavailable in our copy. (LLM, conf=0.82)
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Self-citationIMPORTANCIA DE LA FARMACOMETRÍA EN EL DESARROLLO DE PRODUCTOS BIOLÓGICOS
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- Authors
- Lledo‐Garcia, R., Dixon, K., Shock, A., & Oliver, R.
- Affiliations
- UCB Pharma Slough UK
- UCB Pharma (United Kingdom) (GB)
- ORCID
- Shock, Anthony
- Venue
- CPT: Pharmacometrics & Systems Pharmacology
- Publisher
- Wiley
- Published
- 2021-11-23
- Volume
- 11
- Issue
- 1
- Pages
- 116-128
- ISSN
- 2163-8306 (ISSN-L)
- PMC
- PMC8752106
- OpenAlex
- W3210500969
- Cited by
- 18
- References
- 52
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 1
- FWCI
- 1.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- CPT Pharmacometrics & Systems Pharmacology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- rozanolixizumab, neonatal Fc receptor, pharmacokinetic-pharmacodynamic modeling, IgG removal, first-in-human dose selection, intravenous administration
- MeSH terms
- Animals, Computer Simulation, Dose-Response Relationship, Drug, Humans, Immunoglobulin G, Macaca fascicularis, Models, Biological, Receptors, Fc, Histocompatibility Antigens Class I, Antibodies, Monoclonal, Humanized
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