Physiology‐based pharmacokinetic model with relative transcriptomics to evaluate tissue distribution and receptor occupancy of anifrolumab
Abstract Type I interferons contribute to the pathogenesis of several autoimmune disorders, including systemic lupus erythematosus (SLE), systemic sclerosis, cutaneous lupus erythematosus, and myositis. Anifrolumab is a monoclonal antibody that binds to subunit 1 of the type I interferon receptor (I...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13245 |
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| author | Pradeep Sharma David W. Boulton Lynn N. Bertagnolli Weifeng Tang |
| author_facet | Pradeep Sharma David W. Boulton Lynn N. Bertagnolli Weifeng Tang |
| author_sort | Pradeep Sharma |
| collection | DOAJ |
| description | Abstract Type I interferons contribute to the pathogenesis of several autoimmune disorders, including systemic lupus erythematosus (SLE), systemic sclerosis, cutaneous lupus erythematosus, and myositis. Anifrolumab is a monoclonal antibody that binds to subunit 1 of the type I interferon receptor (IFNAR1). Results of phase IIb and phase III trials led to the approval of intravenous anifrolumab 300 mg every 4 weeks (Q4W) alongside standard therapy in patients with moderate‐to‐severe SLE. Here, we built a population physiology‐based pharmacokinetic (PBPK) model of anifrolumab by utilizing the physiochemical properties of anifrolumab, binding kinetics to the Fc gamma neonatal receptor, and target‐mediated drug disposition properties. A novel relative transcriptomics approach was employed to determine IFNAR1 expression in tissues (blood, skin, gastrointestinal tract, lungs, and muscle) using mRNA abundances from bioinformatic databases. The IFNAR1 expression and PBPK model were validated by testing their ability to predict clinical pharmacokinetics over a large dose range from different clinical scenarios after subcutaneous and intravenous anifrolumab dosing. The validated PBPK model predicted high unbound local concentrations of anifrolumab in blood, skin, gastrointestinal tract, lungs, and muscle, which exceeded its IFNAR1 dissociation equilibrium constant values. The model also predicted high IFNAR1 occupancy with subcutaneous and intravenous anifrolumab dosing. The model predicted more sustained IFNAR1 occupancy ≥90% with subcutaneous anifrolumab 120 mg once‐weekly dosing vs. intravenous 300 mg Q4W dosing. The results informed the dosing of phase III studies of anifrolumab in new indications and present a novel approach to PBPK modeling coupled with relative transcriptomics in simulating pharmacokinetics of therapeutic monoclonal antibodies. |
| format | Article |
| id | doaj-art-6eae4ea9280b4de9a344f4d1d6c2c2d7 |
| institution | Kabale University |
| issn | 2163-8306 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj-art-6eae4ea9280b4de9a344f4d1d6c2c2d72025-01-07T20:48:59ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062025-01-0114110511710.1002/psp4.13245Physiology‐based pharmacokinetic model with relative transcriptomics to evaluate tissue distribution and receptor occupancy of anifrolumabPradeep Sharma0David W. Boulton1Lynn N. Bertagnolli2Weifeng Tang3Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences R&D, AstraZeneca Cambridge UKClinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences R&D, AstraZeneca Gaithersburg Maryland USAClinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences R&D, AstraZeneca Gaithersburg Maryland USAClinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences R&D, AstraZeneca Gaithersburg Maryland USAAbstract Type I interferons contribute to the pathogenesis of several autoimmune disorders, including systemic lupus erythematosus (SLE), systemic sclerosis, cutaneous lupus erythematosus, and myositis. Anifrolumab is a monoclonal antibody that binds to subunit 1 of the type I interferon receptor (IFNAR1). Results of phase IIb and phase III trials led to the approval of intravenous anifrolumab 300 mg every 4 weeks (Q4W) alongside standard therapy in patients with moderate‐to‐severe SLE. Here, we built a population physiology‐based pharmacokinetic (PBPK) model of anifrolumab by utilizing the physiochemical properties of anifrolumab, binding kinetics to the Fc gamma neonatal receptor, and target‐mediated drug disposition properties. A novel relative transcriptomics approach was employed to determine IFNAR1 expression in tissues (blood, skin, gastrointestinal tract, lungs, and muscle) using mRNA abundances from bioinformatic databases. The IFNAR1 expression and PBPK model were validated by testing their ability to predict clinical pharmacokinetics over a large dose range from different clinical scenarios after subcutaneous and intravenous anifrolumab dosing. The validated PBPK model predicted high unbound local concentrations of anifrolumab in blood, skin, gastrointestinal tract, lungs, and muscle, which exceeded its IFNAR1 dissociation equilibrium constant values. The model also predicted high IFNAR1 occupancy with subcutaneous and intravenous anifrolumab dosing. The model predicted more sustained IFNAR1 occupancy ≥90% with subcutaneous anifrolumab 120 mg once‐weekly dosing vs. intravenous 300 mg Q4W dosing. The results informed the dosing of phase III studies of anifrolumab in new indications and present a novel approach to PBPK modeling coupled with relative transcriptomics in simulating pharmacokinetics of therapeutic monoclonal antibodies.https://doi.org/10.1002/psp4.13245 |
| spellingShingle | Pradeep Sharma David W. Boulton Lynn N. Bertagnolli Weifeng Tang Physiology‐based pharmacokinetic model with relative transcriptomics to evaluate tissue distribution and receptor occupancy of anifrolumab CPT: Pharmacometrics & Systems Pharmacology |
| title | Physiology‐based pharmacokinetic model with relative transcriptomics to evaluate tissue distribution and receptor occupancy of anifrolumab |
| title_full | Physiology‐based pharmacokinetic model with relative transcriptomics to evaluate tissue distribution and receptor occupancy of anifrolumab |
| title_fullStr | Physiology‐based pharmacokinetic model with relative transcriptomics to evaluate tissue distribution and receptor occupancy of anifrolumab |
| title_full_unstemmed | Physiology‐based pharmacokinetic model with relative transcriptomics to evaluate tissue distribution and receptor occupancy of anifrolumab |
| title_short | Physiology‐based pharmacokinetic model with relative transcriptomics to evaluate tissue distribution and receptor occupancy of anifrolumab |
| title_sort | physiology based pharmacokinetic model with relative transcriptomics to evaluate tissue distribution and receptor occupancy of anifrolumab |
| url | https://doi.org/10.1002/psp4.13245 |
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