title: Mechanistic modeling of antigen sink effect for mavrilimumab following intravenous administration in patients with rheumatoid arthritis.
abstract: Mavrilimumab is a fully human monoclonal antibody that binds to granulocyte-macrophage colony stimulating factor receptor α (GM-CSFRα) with high affinity and specificity and has potential application in various inflammatory diseases. The objective of this investigation was to develop a mechanistic population model to characterize the pharmacokinetics of mavrilimumab, the GM-CSFRα-mediated clearance, and receptor occupancy following single intravenous dosing to patients with rheumatoid arthritis. The internalization rate of mavrilimumab-GM-CSFRα complex was fixed to a value determined from quantitative confocal fluorescent imaging. The estimated typical first-order clearance and the central and peripheral distribution volumes were 3.79 mL/kg/d, 39.6 mL/kg, and 50.3 mL/kg, respectively. The systemic GM-CSFRα expression level was estimated to be 0.0782 nM, and the equilibrium dissociation constant (0.103 nM) was in good agreement with the monovalent affinity determined by surface plasmon resonance. By fitting to the observed pharmacokinetic data, the mechanistic model predicted that systemically greater than 90% GM-CSFRα blockade by mavrilimumab was achieved and maintained up to 4, 7, and 11 weeks following single 1-, 3-, and 10-mg/kg administrations, respectively. Posterior visual predictive check and bootstrapping suggest that the mechanistic model is reasonably robust and can be used to predict mavrilimumab exposure under various scenarios for future clinical trial design.
authors.affiliation: MedImmune, Hayward, CA 94545, USA. wangbi@medimmune.com
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Lau
authors.forename: Meina
authors.initials: M
authors.lastname: Liang
authors.forename: Inna
authors.initials: I
authors.lastname: Vainshtein
authors.forename: Mikhail
authors.initials: M
authors.lastname: Zusmanovich
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Fabio
authors.initials: F
authors.lastname: Magrini
authors.forename: Matthew
authors.initials: M
authors.lastname: Sleeman
authors.forename: Lorin
authors.initials: L
authors.lastname: Roskos
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000941:Antigens / Q000008:administration & dosage*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053650:Interleukin-3 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism*; D008297:Male
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000941:Antigens; D053650:Interleukin-3 Receptor alpha Subunit; C561644:mavrilimumab