title: Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis.
abstract: OBJECTIVE
  Inhibition of the receptor activator of nuclear factor κ-B ligand (RANKL) is a therapeutic target for treatment of bone disorders associated with increased bone resorption, such as osteoporosis. The objective of this analysis was to characterize the population pharmacokinetics of denosumab (AMG 162; Prolia®), a fully human IgG2 monoclonal antibody that binds to RANKL, in healthy subjects and postmenopausal women with osteopenia or osteoporosis.
  
  
  METHODS
  A total of 22944 serum free denosumab concentrations from 495 healthy subjects and 1069 postmenopausal women with osteopenia or osteoporosis were pooled. Denosumab was administered as either a single intravenous dose (n = 36), a single subcutaneous dose (n = 469) or multiple subcutaneous doses (n = 1059), ranging from 0.01 to 3 mg/kg (or 6-210 mg as fixed mass dosages), every 3 or 6 months for up to 48 months. An open, two-compartment pharmacokinetic model with a quasi-steady-state approximation of the target-mediated drug disposition model was used to describe denosumab pharmacokinetics, using NONMEM Version 7.1.0 software. Subcutaneous absorption was characterized by the first-order absorption rate constant (k(a)), with constant absolute bioavailability over the range of doses that were evaluated. Clearance and volume of distribution parameters were scaled by body weight, using a power model. Model evaluation was performed through visual predictive checks.
  
  
  RESULTS
  The subcutaneous bioavailability of denosumab was 64%, and the k(a) was 0.00883 h-1. The central volume of distribution and linear clearance were 2.49 L/66 kg and 3.06 mL/h/66 kg, respectively. The baseline RANKL level, quasi-steady-state constant and RANKL degradation rate were 614 ng/mL, 138 ng/mL and 0.00148 h-1, respectively. Between-subject variability in model parameters was moderate. A fixed dose of 60 mg provided RANKL inhibition similar to that achieved by equivalent body weight-based dosing. The effects of age and race on the area under the serum concentration-time curve of denosumab were less than 15% over the range of covariate values that were evaluated.
  
  
  CONCLUSIONS
  The non-linearity in denosumab pharmacokinetics is probably due to RANKL binding, and denosumab dose adjustment based on the patient demographics is not warranted.
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Liviawati
authors.initials: L
authors.lastname: Sutjandra
authors.forename: Rachelle D
authors.initials: RD
authors.lastname: Rodriguez
authors.forename: Sameer
authors.initials: S
authors.lastname: Doshi
authors.forename: Mark
authors.initials: M
authors.lastname: Ma
authors.forename: Mark C
authors.initials: MC
authors.lastname: Peterson
authors.forename: Graham R
authors.initials: GR
authors.lastname: Jang
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chow
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Pérez-Ruixo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents / Q000097:blood / Q000493:pharmacokinetics*; D001851:Bone Diseases, Metabolic / Q000097:blood* / Q000188:drug therapy; D000069448:Denosumab; D005260:Female; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D010024:Osteoporosis / Q000097:blood* / Q000188:drug therapy; D017698:Postmenopause / Q000097:blood; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D053245:RANK Ligand; D000069448:Denosumab
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