Pharmacokinetic‐pharmacodynamic modelling of the anti‐FcRn monoclonal antibody rozanolixizumab: Translation from preclinical stages to the clinic
Abstract 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 stu...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-01-01
|
| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12739 |
| _version_ | 1830209391598501888 |
|---|---|
| author | Rocio Lledo‐Garcia Kate Dixon Anthony Shock Ruth Oliver |
| author_facet | Rocio Lledo‐Garcia Kate Dixon Anthony Shock Ruth Oliver |
| author_sort | Rocio Lledo‐Garcia |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-18T05:06:48Z |
| format | Article |
| id | doaj.art-86e0c900926549b79d038e9285220507 |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-12-18T05:06:48Z |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-86e0c900926549b79d038e92852205072022-12-21T21:19:59ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062022-01-0111111612810.1002/psp4.12739Pharmacokinetic‐pharmacodynamic modelling of the anti‐FcRn monoclonal antibody rozanolixizumab: Translation from preclinical stages to the clinicRocio Lledo‐Garcia0Kate Dixon1Anthony Shock2Ruth Oliver3UCB Pharma Slough UKUCB Pharma Slough UKUCB Pharma Slough UKUCB Pharma Slough UKAbstract 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.https://doi.org/10.1002/psp4.12739 |
| spellingShingle | Rocio Lledo‐Garcia Kate Dixon Anthony Shock Ruth Oliver Pharmacokinetic‐pharmacodynamic modelling of the anti‐FcRn monoclonal antibody rozanolixizumab: Translation from preclinical stages to the clinic CPT: Pharmacometrics & Systems Pharmacology |
| title | Pharmacokinetic‐pharmacodynamic modelling of the anti‐FcRn monoclonal antibody rozanolixizumab: Translation from preclinical stages to the clinic |
| title_full | Pharmacokinetic‐pharmacodynamic modelling of the anti‐FcRn monoclonal antibody rozanolixizumab: Translation from preclinical stages to the clinic |
| title_fullStr | Pharmacokinetic‐pharmacodynamic modelling of the anti‐FcRn monoclonal antibody rozanolixizumab: Translation from preclinical stages to the clinic |
| title_full_unstemmed | Pharmacokinetic‐pharmacodynamic modelling of the anti‐FcRn monoclonal antibody rozanolixizumab: Translation from preclinical stages to the clinic |
| title_short | Pharmacokinetic‐pharmacodynamic modelling of the anti‐FcRn monoclonal antibody rozanolixizumab: Translation from preclinical stages to the clinic |
| title_sort | pharmacokinetic pharmacodynamic modelling of the anti fcrn monoclonal antibody rozanolixizumab translation from preclinical stages to the clinic |
| url | https://doi.org/10.1002/psp4.12739 |
| work_keys_str_mv | AT rociolledogarcia pharmacokineticpharmacodynamicmodellingoftheantifcrnmonoclonalantibodyrozanolixizumabtranslationfrompreclinicalstagestotheclinic AT katedixon pharmacokineticpharmacodynamicmodellingoftheantifcrnmonoclonalantibodyrozanolixizumabtranslationfrompreclinicalstagestotheclinic AT anthonyshock pharmacokineticpharmacodynamicmodellingoftheantifcrnmonoclonalantibodyrozanolixizumabtranslationfrompreclinicalstagestotheclinic AT rutholiver pharmacokineticpharmacodynamicmodellingoftheantifcrnmonoclonalantibodyrozanolixizumabtranslationfrompreclinicalstagestotheclinic |