ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1631034
This article is part of the Research TopicIntegrated PK/PD and Drug Metabolism Approaches in Drug Development and EvaluationView all 4 articles
Population Pharmacokinetics/Pharmacodynamics Analysis Confirming Biosimilarity of SB16 to Reference Denosumab
Provisionally accepted
- 1Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- 2Department of Medical Science and Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Republic of Korea
- 3Samsung Bioepis Co., Ltd, Incheon, Republic of Korea
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Background: This analysis aims to evaluate the population pharmacokinetics (PK) and pharmacodynamics (PD) of denosumab and applied a population PK/PD approach to assess the biosimilarity of SB16 in comparison to reference product, denosumab (DEN).Methods: Pooled serum concentrations data for SB16 and DEN from male healthy volunteers (HV) in the Phase I and from postmenopausal women with osteoporosis (PMO) Phase III studies, along with lumbar spine bone mineral density (BMD) data from Phase III study, were analyzed using a nonlinear mixed effects population PK/PD sequential modeling approach. The effects of key patient variables on PK/PD parameters were assessed. Treatment effects on clearance (CL) were retained in the model, regardless of statistical significance, to enable comparative simulation between SB16 and DEN. Modeling and simulation were performed using Monolix Suite™.Results: A two-compartment target-mediated drug disposition (TMDD) model with quasi-steady state (QSS) approximation and first-order absorption adequately characterized the PK profile of denosumab. An indirect response model with maximal inhibitory function captured changes in lumbar spine BMD following treatment.The study population had a minimal effect on drug exposure and on changes in BMD, with < 5% difference.Race and body weight accounted for up to 19% and 45% of the variability in drug exposure, respectively, but these differences translated into less than a 2% difference in changes in BMD for each covariate. The treatment group (SB16 vs. DEN) was not identified as a significant covariate. Including this factor on CL in the final PK/PD model, irrespective of its statistical significance, did not affect the PK/PD parameter estimates. Comparative simulations showed similar results for both treatment groups.The developed TMDD-QSS model with indirect response model adequately characterized the PK/PD profile of denosumab. Covariate effects, including study population (HV vs. PMO), age, and race showed no clinically meaningful impact on treatment outcomes. Covariate analysis and simulation results revealed no significant differences in PK/PD parameters between SB16 and DEN. The similarity in the PK profile and change in lumbar spine BMD between SB16 and DEN were demonstrated, supporting the potential for SB16 to be substituted for the reference product in the treatment of osteoporosis.
Keywords: Denosumab, biosimilar, Target-mediated drug disposition, Osteoporosis, PK/PD modeling and simulation, Monolix
Received: 19 May 2025; Accepted: 21 Jul 2025.
Copyright: © 2025 Choi, Park, Baek, Jung and Lim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Hyeong-Seok Lim, Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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