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

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Abstract

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 (ka), 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 ka 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.

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Acknowledgements

The authors thank Ed Lee and Leonid Gibiansky for the support and comments they provided during the completion of this analysis. The authors also thank the hundreds of patients, investigators, and medical, nursing and laboratory staff who participated in the clinical studies that were included in the present analysis.

This study was sponsored by Amgen Inc., which was involved in the study design; the data collection, analysis and interpretation; the writing of the manuscript; and the decision to submit the manuscript for publication. Liviawati Sutjandra, Sameer Doshi, Mark Ma, Graham Jang, Andrew Chow and Juan José Pérez-Ruixo were employees of Amgen Inc. and owned stock in Amgen Inc. at the time when the analysis was conducted. Rachelle Rodriguez and Mark Peterson are former employees of Amgen Inc. The authors have no other conflicts of interest to declare.

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  1. Amgen Inc., Thousand Oaks, California, USA

    Liviawati Sutjandra, Rachelle D. Rodriguez, Sameer Doshi, Mark Ma, Mark C. Peterson, Graham R. Jang, Andrew T. Chow &  Juan José Pérez-Ruixo

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  1. Liviawati Sutjandra
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Correspondence to Juan José Pérez-Ruixo.

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Sutjandra, L., Rodriguez, R.D., Doshi, S. et al. Population Pharmacokinetic Meta-Analysis of Denosumab in Healthy Subjects and Postmenopausal Women with Osteopenia or Osteoporosis. Clin Pharmacokinet 50, 793–807 (2011). https://doi.org/10.2165/11594240-000000000-00000

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