A multi‐model approach to predict efficacious clinical dose for an anti‐TGF‐β antibody (GC2008) in the treatment of osteogenesis imperfecta. (27th September 2022)

• Record Type: Journal Article
• Authors: Mavroudis, Panteleimon D.; Pillai, Nikhil; Wang, Qingping; Pouzin, Clemence; Greene, Benjamin; Fretland, Jennifer
• Is Part Of: CPT: pharmacometrics & systems pharmacology. Volume 11:Number 11(2022)
• Page Start: 1485
• Page End: 1496
• Publication Date: 2022-09-27
• Subjects: Pharmacokinetics -- Periodicals; Pharmacology -- Periodicals; Pharmacokinetics; Periodicals; 615.05
• DOI: 10.1002/psp4.12857
• Languages: English
• ISSNs: 2163-8306

Abstract

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 multidisciplinary 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 patients with OI. In this work, we have developed a multitiered 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 patients with OI. Furthermore, a physiologically‐based pharmacokinetic model incorporating GC2008 and the body's physiological properties was developed and used to predict a GC2008 dose that would decrease the 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 of GC2008 in humans. The different modeling efforts predicted a similar range of pharmacologically relevant doses in patients with OI providing an informed approach for an early clinical dose setting.