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BackgroundEfpeglenatide (HM11260C) is a long-acting GLP-1 receptor agonist under development for obesity. A population pharmacokinetic (PK) analysis was conducted to characterize its PK properties and evaluate covariate effects to support clinical dosing strategies.MethodsPooled PK data from six clinical studies in participants with type 2 diabetes or obesity were analyzed using nonlinear mixed-effects modeling (NONMEM). Covariate effects, model diagnostics, and simulations were used to assess exposure and dosing strategies.ResultsA two-compartment model with dual absorption pathways adequately described the data. Body weight and disease status influenced absorption and clearance; however, predicted exposure differences across weight percentiles and demographic subgroups were modest and within conventional bioequivalence limits. Simulations suggested approximately dose-proportional increases across the evaluated dose range with once-weekly administration and supported the feasibility of stepwise dose-escalation.ConclusionEfpeglenatide PK was well characterized across type 2 diabetes and obesity populations. Although some covariates affected PK parameters, their impact on exposure was not clinically meaningful. These results support a uniform dosing strategy without routine dose adjustment and provide quantitative evidence for stepwise dose escalation in ongoing clinical development for obesity.

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). 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™. 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.

Purpose: This analysis aimed to characterize the exposure–response relationship of bevacizumab in non-small-cell lung cancer (NSCLC) and evaluate the efficacy of SB8, a bevacizumab biosimilar, and Avastin ® , the reference bevacizumab sourced from the European Union (EU), based on the exposure reported in a comparative phase III efficacy and safety study (EudraCT, 2015-004026-34; NCT 02754882). Materials and methods: The overall survival (OS) and progression-free survival (PFS) data from 224 patients with steady-state trough concentrations (C ss,trough ) were analyzed. A parametric time-to-event (TTE) model was developed using NONMEM ® , and the effects of treatments (SB8 and bevacizumab-EU) and patient demographic and clinical covariates on OS and PFS were evaluated. Simulations of median OS and PFS by bevacizumab C ss,trough were conducted, and concentrations required to achieve 50% and 90% of the maximum median TTE were computed. Results: A log-logistics model with C ss,trough best described the OS and PFS data. Treatment was not a predictor of the hazard for OS or PFS. Simulations revealed steep exposure–response curves with a phase of rapid rise before saturating to a plateau. The median C ss,trough values of SB8 and bevacizumab-EU reported from the clinical study were on the plateaus of the exposure–response curves. The concentrations required to achieve 50% and 90% of the maximum effect were 82.4 and 92.2 μg/mL, respectively, for OS and 79.7 and 89.1 μg/mL, respectively, for PFS. Conclusion: Simulations based on the constructed TTE models for OS and PFS have well described the exposure–response relationship of bevacizumab in advanced NSCLC. The analysis demonstrated comparable efficacy between SB8 and bevacizumab-EU in terms of OS and PFS based on their exposure levels.

Artificial skin models have emerged as valuable tools for evaluating cosmetic ingredients and developing treatments for skin regeneration. Among them, 3D skin equivalent models (SKEs) using human primary skin cells are widely utilized and supported by standardized testing guidelines. However, primary cells face limitations such as restricted donor availability and challenges in conducting genotype-specific studies. To overcome these issues, recent approaches have focused on differentiating skin cells from human-induced pluripotent stem cells (hiPSCs). In this study, we developed a protocol to differentiate high-purity skin cells, such as fibroblasts (hFIBROs) and keratinocytes (hKERAs), from hiPSCs. To construct the hiPSC-derived SKE (hiPSC-SKE), a dermis was first formed by culturing a collagen and hFIBROs mixture within an insert. Subsequently, hKERAs were seeded onto the dermis, and keratinization was induced under air-liquid culture conditions to establish an epidermis. Histological analysis with hematoxylin and eosin staining confirmed that the hiPSC-SKE recapitulated the layered architecture of native human skin and expressed appropriate epidermal and dermal markers. Moreover, exposure to Triton X-100, a known skin irritant, led to marked epidermal damage and significantly reduced cell viability, validating the model’s functional responsiveness. These findings indicate that the hiPSC-SKE model represents a promising alternative for various skin-related applications, including the replacement of animal testing.

Abstract As research on in vitro cardiotoxicity assessment and cardiac disease modeling becomes more important, the demand for human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is increasing. However, it has been reported that differentiated hPSC-CMs are in a physiologically immature state compared to in vivo adult CMs. Since immaturity of hPSC-CMs can lead to poor drug response and loss of acquired heart disease modeling, various approaches have been attempted to promote maturation of CMs. Here, we confirm that peroxisome proliferator-activated receptor alpha (PPARα), one of the representative mechanisms of CM metabolism and cardioprotective effect also affects maturation of CMs. To upregulate PPARα expression, we treated hPSC-CMs with fenofibrate (Feno), a PPARα agonist used in clinical hyperlipidemia treatment, and demonstrated that the structure, mitochondria-mediated metabolism, and electrophysiology-based functions of hPSC-CMs were all mature. Furthermore, as a result of multi electrode array (MEA)-based cardiotoxicity evaluation between control and Feno groups according to treatment with arrhythmia-inducing drugs, drug response was similar in a dose-dependent manner. However, main parameters such as field potential duration, beat period, and spike amplitude were different between the 2 groups. Overall, these results emphasize that applying matured hPSC-CMs to the field of preclinical cardiotoxicity evaluation, which has become an essential procedure for new drug development, is necessary. Graphical Abstract Graphical Abstract