title: Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors.
abstract: Denosumab (XGEVA®) is a recombinant, fully human IgG2 monoclonal antibody directed against the receptor activator of nuclear factor kappa-B ligand (RANKL) that prevents differentiation of osteoclast precursors into mature osteoclasts and acceleration of bone resorption, resulting in the inhibition of osteoclast activation. Denosumab is indicated for the prevention of skeletal-related events (SREs) in adult patients with bone metastases from solid tumors at the dose of 120 mg administered subcutaneously (SC) every 4 weeks. This review is focused on describing its target-mediated disposition and direct inhibitory effect on bone resorption, as well as the modeling and simulation techniques used to integrate the PKPD information collected during clinical development of denosumab. In addition, this review further discusses the clinical relevance of patient covariate effects on denosumab systemic exposure, target engagement and downstream pharmacodynamics biomarkers, and the rationale for dosing regimen selection for Phase 3 studies. Phase 3 clinical studies demonstrated that denosumab was superior to zoledronic acid in inhibiting bone resorption and, consequently, delaying the time to first SRE by a median of 8.2 months in patients with bone metastases from solid tumors. Thus, denosumab may be considered a better alternative treatment than zoledronic acid for the prevention of SRE in patients with bone metastases from solid tumors.
authors.affiliation: Amgen Inc. Thousand Oaks, California, USA.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Perez Ruixo
authors.forename: Sameer
authors.initials: S
authors.lastname: Doshi
authors.forename: Winnie
authors.initials: W
authors.lastname: Sohn
authors.forename: Andrew
authors.initials: A
authors.lastname: Chow
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D001862:Bone Resorption / Q000188:drug therapy*; D000069448:Denosumab; D006801:Humans; D053245:RANK Ligand / Q000037:antagonists & inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D053245:RANK Ligand; D000069448:Denosumab
keywords: cancer; denosumab; modelling; pharmacodynamics; pharmacokinetics