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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\u2010\u03b2) 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\u2010TGF\u2010\u03b2 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\u2010clinical and clinical PK\/PD data and predict a GC2008 dose that would significantly increase BMD or BVF in patients with OI. Furthermore, a physiologically\u2010based pharmacokinetic model incorporating GC2008 and the body's physiological properties was developed and used to predict a GC2008 dose that would decrease the TGF\u2010\u03b2 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.<\/jats:p>","DOI":"10.1002\/psp4.12857","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T09:58:56Z","timestamp":1661421536000},"page":"1485-1496","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A multi\u2010model approach to predict efficacious clinical dose for an <scp>anti\u2010TGF<\/scp>\u2010\u03b2 antibody (<scp>GC2008<\/scp>) in the treatment of osteogenesis imperfecta"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0512-4147","authenticated-orcid":false,"given":"Panteleimon D.","family":"Mavroudis","sequence":"first","affiliation":[{"name":"Quantitative Pharmacology DMPK, Sanofi US  Waltham Massachusetts 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