Population Pharmacokinetic Meta-Analysis of Denosumab in Healthy Subjects and Postmenopausal Women with Osteopenia or Osteoporosis

• Published in: Clinical pharmacokinetics Vol. 50; no. 12; pp. 793 - 807
• Main Authors: Sutjandra, Liviawati, Rodriguez, Rachelle D., Doshi, Sameer, Ma, Mark, Peterson, Mark C., Jang, Graham R., Chow, Andrew T., Pérez-Ruixo, Juan José
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2011; Adis International; Wolters Kluwer Health, Inc; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal, Humanized; Biological and medical sciences; Bone Density Conservation Agents - blood; Bone Density Conservation Agents - pharmacokinetics; Bone Diseases, Metabolic - blood; Bone Diseases, Metabolic - drug therapy; Denosumab; Diagnosis; Diseases of the osteoarticular system; Drug therapy; Female; General pharmacology; Health aspects; Humans; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Original Research Article; Osteopenia; Osteoporosis; Osteoporosis - blood; Osteoporosis - drug therapy; Osteoporosis. Osteomalacia. Paget disease; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Postmenopausal women; Postmenopause - blood; RANK Ligand - antagonists & inhibitors; Young Adult; Spain; Omalizumab; Ustekinumab; Denosumab; Stochastic Approximation Expectation Maximization; Conditional Weighted Residual; Human; Population pharmacokinetics; Healthy subject; Menopause; Diseases of the osteoarticular system; Monoclonal antibody; Metaanalysis; Immunomodulator; Osteoporosis; Postmenopause; Adult; Female; Woman; Osteopenia
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.2165/11594240-000000000-00000

Background and Objective: Inhibition of the receptor activator of nuclear factor k-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 post-menopausal 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 614ng/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.