Population pharmacokinetics/pharmacodynamics analysis confirming biosimilarity of SB16 to reference denosumab
BackgroundThis 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).MethodsPooled serum concentrations data for SB16 and DE...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1631034/full |
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| author | Seungchan Choi Seungchan Choi Suemin Park Jinah Jung Siook Baek Hyeong-Seok Lim Hyeong-Seok Lim |
| author_facet | Seungchan Choi Seungchan Choi Suemin Park Jinah Jung Siook Baek Hyeong-Seok Lim Hyeong-Seok Lim |
| author_sort | Seungchan Choi |
| collection | DOAJ |
| description | BackgroundThis 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).MethodsPooled 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™.ResultsA 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.ConclusionThe 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. |
| format | Article |
| id | doaj-art-e06b307b7222479d958bd6f1ff3cd0be |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-e06b307b7222479d958bd6f1ff3cd0be2025-08-20T03:44:18ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-08-011610.3389/fphar.2025.16310341631034Population pharmacokinetics/pharmacodynamics analysis confirming biosimilarity of SB16 to reference denosumabSeungchan Choi0Seungchan Choi1Suemin Park2Jinah Jung3Siook Baek4Hyeong-Seok Lim5Hyeong-Seok Lim6Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaDepartment of Medical Science and Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaDepartment of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaSamsung Bioepis Co., Ltd., Incheon, Republic of KoreaSamsung Bioepis Co., Ltd., Incheon, Republic of KoreaDepartment of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaDepartment of Medical Science and Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaBackgroundThis 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).MethodsPooled 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™.ResultsA 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.ConclusionThe 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.https://www.frontiersin.org/articles/10.3389/fphar.2025.1631034/fulldenosumabbiosimilartarget-mediated drug dispositionosteoporosisPK/PD modeling and simulationmonolix |
| spellingShingle | Seungchan Choi Seungchan Choi Suemin Park Jinah Jung Siook Baek Hyeong-Seok Lim Hyeong-Seok Lim Population pharmacokinetics/pharmacodynamics analysis confirming biosimilarity of SB16 to reference denosumab Frontiers in Pharmacology denosumab biosimilar target-mediated drug disposition osteoporosis PK/PD modeling and simulation monolix |
| title | Population pharmacokinetics/pharmacodynamics analysis confirming biosimilarity of SB16 to reference denosumab |
| title_full | Population pharmacokinetics/pharmacodynamics analysis confirming biosimilarity of SB16 to reference denosumab |
| title_fullStr | Population pharmacokinetics/pharmacodynamics analysis confirming biosimilarity of SB16 to reference denosumab |
| title_full_unstemmed | Population pharmacokinetics/pharmacodynamics analysis confirming biosimilarity of SB16 to reference denosumab |
| title_short | Population pharmacokinetics/pharmacodynamics analysis confirming biosimilarity of SB16 to reference denosumab |
| title_sort | population pharmacokinetics pharmacodynamics analysis confirming biosimilarity of sb16 to reference denosumab |
| topic | denosumab biosimilar target-mediated drug disposition osteoporosis PK/PD modeling and simulation monolix |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1631034/full |
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