https://pubmed.ncbi.nlm.nih.gov/36004727/
Panteleimo Mavroudis, Nikhil Pillai, Qingping Wang, Clemence Pouzin, Benjamin Greene, Jennifer Fretland
CPT Pharmacometrics Syst Pharmacol. 2022 Aug 25.
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous group of inherited bone dysplasias characterized by reduced skeletal mass and bone fragility. Although the primary manifestation of the disease involves the skeleton, OI is a generalized connective tissue disorder that requires a multi-disciplinary treatment approach. Recent studies indicate that application of a transforming growth factor beta (TGF-β) neutralizing antibody increased bone volume fraction (BVF) and strength in an OI mouse model and improved bone mineral density (BMD) in a small cohort of OI patients. In this work, we've developed a multi-tiered quantitative pharmacology approach to predict human efficacious dose of a new anti-TGF-β antibody drug candidate (GC2008). This method aims to translate GC2008 Pharmacokinetic/Pharmacodynamic (PK/PD) relationship in patients, using a number of appropriate mathematical models and available preclinical and clinical data. Compartmental PK linked with an indirect PD effect model was used to characterize both pre-clinical and clinical PK/PD data and predict a GC2008 dose that would significantly increase BMD or BVF in OI patients. Furthermore, a physiologically based pharmacokinetic (PBPK) model incorporating GC2008 and body's physiological properties was developed and used to predict a GC2008 dose that would decrease TGF-β level in bone to that of healthy individuals. By using multiple models, we aim to reveal information for different aspects of OI disease that will ultimately lead to a more informed dose projection for GC2008 in humans data. The different modeling efforts predicted a similar range of pharmacologically relevant doses in OI patients providing an informed approach for early clinical dose setting.
This article is protected by copyright. All rights reserved.
https://pubmed.ncbi.nlm.nih.gov/36004727/ Panteleimo Mavroudis, Nikhil Pillai, Qingping Wang, Clemence Pouzin, Benjamin Greene, Jennifer Fretland CPT Pharmacometrics Syst Pharmacol. 2022 Aug 25.
Abstract Osteogenesis imperfecta (OI) is a heterogeneous group of inherited bone dysplasias characterized by reduced skeletal mass and bone fragility. Although the primary manifestation of the disease involves the skeleton, OI is a generalized connective tissue disorder that requires a multi-disciplinary treatment approach. Recent studies indicate that application of a transforming growth factor beta (TGF-β) neutralizing antibody increased bone volume fraction (BVF) and strength in an OI mouse model and improved bone mineral density (BMD) in a small cohort of OI patients. In this work, we've developed a multi-tiered quantitative pharmacology approach to predict human efficacious dose of a new anti-TGF-β antibody drug candidate (GC2008). This method aims to translate GC2008 Pharmacokinetic/Pharmacodynamic (PK/PD) relationship in patients, using a number of appropriate mathematical models and available preclinical and clinical data. Compartmental PK linked with an indirect PD effect model was used to characterize both pre-clinical and clinical PK/PD data and predict a GC2008 dose that would significantly increase BMD or BVF in OI patients. Furthermore, a physiologically based pharmacokinetic (PBPK) model incorporating GC2008 and body's physiological properties was developed and used to predict a GC2008 dose that would decrease TGF-β level in bone to that of healthy individuals. By using multiple models, we aim to reveal information for different aspects of OI disease that will ultimately lead to a more informed dose projection for GC2008 in humans data. The different modeling efforts predicted a similar range of pharmacologically relevant doses in OI patients providing an informed approach for early clinical dose setting.
This article is protected by copyright. All rights reserved.