https://ir.ymlib.yonsei.ac.kr/handle/22282913/181720 Wed, 15 Apr 2026 21:15:31 GMT 2026-04-15T21:15:31Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/209491 Title: Model-informed development of bacteriophage therapy: bridging in vitro and in vivo efficacy against multidrug-resistant Pseudomonas aeruginosa Authors: Cha, Jun Seok; Kim, Kyungnam; You, Hwa Jeong; Kim, Dasom; Park, Hyun Hee; Heo, Sujin; Kim, Choon Ok; Jin, Byung Hak; Yong, Dongeun; Chae, Dongwoo Abstract: Bacteriophages are emerging as promising alternatives to antibiotics for multidrug-resistant (MDR) infections. However, their unique pharmacokinetic and pharmacodynamic (PKPD) properties arising from host-dependent amplification present challenges for dose selection and clinical translation. Here, we present a mechanistic PKPD model informed by in vitro kinetic assays and in vivo mouse studies of phage therapy targeting MDR Pseudomonas aeruginosa. The model extends the classical predator-prey model by addressing dormancy-related bacterial persistence and partitioning bacterial subpopulations based on phage susceptibility profiles. Simulations revealed a non-monotonous dose-exposure curve driven by dose-dependent reduction of phage replication and the importance of cross-resistance in selecting optimal phage cocktails. In vivo, host immunity was identified as a crucial component in inhibiting bacterial regrowth, with bistable outcomes dependent on initial bacterial load and immune competence. Dose-ranging simulations under varying immune statuses suggest that long-term bacterial load is solely determined by host immune function. However, higher doses transiently reduce bacterial load to a greater extent and thereby suppress immune activation. In immunocompetent hosts, phage cocktails can enhance maximal bacterial load reduction when administered at doses higher than a critical threshold. In conclusion, our PKPD framework enables optimal selection of phage cocktails and dosing regimens, supports rational design of first-in-human trials of phage therapy, and potentially advances model-informed drug development for replication-competent biologics.IMPORTANCEIn this study, we construct an integrative model of phage-bacteria dynamics and investigate whether its calibration to in vitro kinetic assay data can inform the rational design of phage therapy regimens and cocktails. Our findings demonstrate a dose range within which lower phage doses yield higher long-term exposure, presenting a fundamentally different framework for dose optimization. Analysis of phage cocktails reveals that combining phages with low cross-resistance delays the regrowth of phage-resistant bacteria in vitro. The extended in vivo model elucidates key differences between in vitro and in vivo outcomes and highlights the importance of the host's immune response in suppressing the growth of phage-resistant bacteria. Phage cocktails to combat phage resistance are therefore of less importance in immune-competent individuals but can enhance bacterial killing when administered at sufficiently high doses. We propose that this modeling framework holds potential for model-informed drug development by quantitatively characterizing bacteria-phage dynamics using preclinical data. Furthermore, it may facilitate the interpretation of in vivo therapeutic outcomes through a mechanistic understanding derived from in vitro observations. Mon, 01 Dec 2025 00:00:00 GMT https://ir.ymlib.yonsei.ac.kr/handle/22282913/209491 2025-12-01T00:00:00Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/209971 Title: Evaluating current status of network pharmacology for herbal medicine focusing on identifying mechanisms and therapeutic effects Authors: Lee, Won-Yung; Park, Kwang-Il; Bak, Seon-Been; Lee, Seungho; Bae, Su-Jin; Kim, Min-Jin; Park, Sun-Dong; Kim, Choon Ok; Kim, Ji-Hwan; Kim, Young Woo; Kim, Chang-Eop Abstract: Introduction: Network pharmacology has gained significant traction as a tool for identifying the mechanisms and therapeutic effects of herbal medicines. However, despite the usefulness of these approaches, their diversity underscores the critical need for a systematic evaluation to ensure consistency and reliability. Objectives: We aimed to evaluate the network pharmacological analyses, focusing on identifying the mechanisms and therapeutic effects of herbal medicines. Methods: We employed a comprehensive approach involving systematic data retrieval, network construction, and analysis. Herbal compounds and their targets were meticulously extracted from five distinct network pharmacology databases to ensure extensive coverage and high data reliability. Advanced network-based methods were used to identify key herbal targets and predict therapeutic effects, thereby enriching the depth and breadth of the analysis. Experimental validation was performed on prostate cancer models to substantiate the computational predictions. Results: The results of the recapitulating task for known herbal ingredient targets revealed distinct patterns in performance and coverage based on network construction and aggregation methods. We performed the same analysis to identify herbal targets and found that network centrality, path counts, and downweighted path counts had their own pros and cons. By comparing network-based methods, we found that considering the impact on the multiscale interactome yielded the highest accuracy in discriminating known therapeutic effects. Using optimal conditions, we successfully identified new indications for herbal medicines and validated these findings through follow-up in vitro and in vivo experiments. Conclusion: This study presents the first comprehensive and critical evaluation of the current network pharmacology analyses in the field of herbal medicine and provides valuable guidance for continued advances in the elucidation of the mechanisms and therapeutic effects. (c) 2024 Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Wed, 01 Oct 2025 00:00:00 GMT https://ir.ymlib.yonsei.ac.kr/handle/22282913/209971 2025-10-01T00:00:00Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/207320 Title: Bioequivalence of a Donepezil/Memantine 10/20 mg Fixed-Dose Combination Versus Single-Component Tablets in Healthy Korean Males Authors: Choi, Minkyu; Jin, Byung Hak; Keum, Do Hoon; Mo, Kyoung Hoon; Park, Min Soo; Lee, Juhwan; Park, Sungjin; Kim, Choon Ok Abstract: A fixed-dose combination (FDC) tablet formulation of donepezil/memantine (10/20 mg) was developed to improve medication compliance in patients with Alzheimer's disease (AD). This study compared the pharmacokinetic (PK) characteristics and safety profiles of an FDC formulation (donepezil/memantine [10/20 mg]) and single components (SCs) of donepezil (10 mg) and memantine (20 mg). In a randomized, open-label, single-dose, 2-way crossover study, 24 healthy Korean participants received a single oral dose of FDC in 1 period and an SC of donepezil and memantine in another period. For PK analysis, blood samples were collected up to 240 hours after administration. The geometric mean ratios and their 90% confidence intervals for the main PK parameters (C-max and AUC(last)) indicated PK equivalence between the FDC and SC formulations. Regarding the safety profile, all adverse events were mild, with no serious adverse events. These findings support the use of an FDC formulation as a viable alternative to SCs of donepezil and memantine, potentially improving treatment adherence in patients with moderate-to-severe AD. Mon, 01 Sep 2025 00:00:00 GMT https://ir.ymlib.yonsei.ac.kr/handle/22282913/207320 2025-09-01T00:00:00Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/209318 Title: Application of population pharmacokinetic modeling of SVG-101 to evaluate proper dose selection Authors: Mo, Kyoung Hoon; Chae, Dongwoo; Jung, Yun Seob; Jin, Byung Hak; Keum, Do Hoon; Choi, Min Kyu; Cha, Jun Seok; Park, Min Soo; Kim, Choon Ok Abstract: Everolimus, an inhibitor of the mammalian target of the rapamycin signaling pathway, is used to treat tuberous sclerosis complex (TSC), certain cancers, and organ transplantation. Although a dispersible formulation has been approved for pediatric patients with TSC-associated seizures, no dispersible everolimus formulation has been approved for adults with swallowing difficulties. This study aimed to evaluate the pharmacokinetics (PK) ofa newly developed dispersible everolimus tablet (SVG101) in healthy adult males and determine an optimal dosing regimen to achieve therapeutic trough concentrations. This randomized, open-label, single-dose, 2 x 2 crossover study included 26 healthy Korean males. The participants received either the reference tablet or SVG101, with a minimum 10-day washout period between treatments. Blood samples were collected up to 144 hours post-dosing. Population PK modeling was performed using a two-compartment model with dual absorption kinetics (zero-order kinetics, followed by first-order kinetics with lag time). The model evaluation demonstrated good agreement between the observed and predicted concentrations, with no significant covariates identified. Simulation of steady-state trough concentrations indicated that daily doses of 3-4 mg of dispersible everolimus resulted in trough levels within the therapeutic range (5-15 ng/mL), whereas the 5 mg dose exceeded this range. These findings suggest that a daily dose of 3-4 mg is appropriate to maintain target trough concentrations in adults. This study supports the development of a dispersible everolimus formulation for adults with swallowing difficulties that can improve adherence and clinical outcomes. Further studies involving diverse patient populations are required to confirm these findings. Mon, 01 Sep 2025 00:00:00 GMT https://ir.ymlib.yonsei.ac.kr/handle/22282913/209318 2025-09-01T00:00:00Z