Translational and Clinical Pharmacology最新文献

{"title":"Clinical data warehouse analysis of clinical laboratory test results of Korean healthy volunteers: does \"not clinically significant\" range of healthy volunteers need modification?","authors":"Cheol Joong Kim, Tak Don Kim, Ye Chan Park, Jin-Gyu Jung, Jung Sunwoo, Jang Hee Hong","doi":"10.12793/tcp.2025.33.e2","DOIUrl":"https://doi.org/10.12793/tcp.2025.33.e2","url":null,"abstract":"<p><p>This study analyzed clinical laboratory test results of healthy Korean volunteers screened for Phase 1 clinical trials at Chungnam National University Hospital. Data from 53 trials conducted between 2019 and 2023 were extracted from the Clinical Data Warehouse and included tests such as white blood cell count, hemoglobin, aspartate aminotransferase, alanine aminotransferase, and creatinine. The study aimed to evaluate whether current ranges for \"not clinically significant (NCS)\" values need modification. Results showed that NCS values often varied between studies, with temporary deviations from normal ranges being common among healthy volunteers, especially those engaged in activities such as heavy weight training or recent dietary excess. Comparative pharmacokinetics and bioequivalence studies made up the majority of trials. The analysis highlighted discrepancies in laboratory criteria application, with implications for screening failure rates. The findings suggest that stricter guidelines might exclude otherwise eligible participants unnecessarily. Establishing consistent NCS criteria could optimize screening and reduce variability across clinical sites. This is the first study to provide insights into clinical lab results for healthy Korean volunteers, emphasizing the need for tailored NCS guidelines in Phase 1 trials.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"33 1","pages":"19-26"},"PeriodicalIF":1.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11976152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144016066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The superiority of likelihood-based confidence interval for variance estimation in a single group.","authors":"Soo-Min Jung, Minkyu Kim, Kyun-Seop Bae","doi":"10.12793/tcp.2025.33.e1","DOIUrl":"https://doi.org/10.12793/tcp.2025.33.e1","url":null,"abstract":"<p><p>The χ² distribution is commonly used for estimating confidence interval (CI) for variance. However, the validity of the CIs from this method is highly dependent on the assumption that the population follows a normal distribution. Additionally, the Wald CI used in this method does not account for the asymmetry. To address this limitation and provide more accurate interval estimates, especially with relatively small sample sizes, a likelihood interval (LI) approach was adopted. The Likelihood-Based Interval R software package was developed to implement this approach. We conducted a simulation to compare 3 methods for interval estimation of variance in a single group, using the luteinizing hormone () data available with the default R installation and random small sample sizes of 10, 20, and 30 from a standard normal distribution: the conventional χ² interval method, the LI method, and the likelihood-based confidence interval (LBCI) method. The average width (standard deviation) of the CIs from the simulation with data was 0.2582 (0.0534) for LBCI, 0.2604 (0.0538) for LI, and 0.2667 (0.0551) for CI, indicating that LBCI produced the narrowest CIs. The interval coverage was 95.24% for CI, 95.38% for LBCI, and 95.45% for LI. In simulations with small sample sizes, LBCI and LI exhibited narrower widths than CI, while the coverage was similar. Therefore, LBCI or LI for variance estimation can be considered a more efficient option than the conventional method.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"33 1","pages":"10-18"},"PeriodicalIF":1.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11976149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of pharmacokinetics of a fixed-dose combination of atorvastatin/ezetimibe 5 mg/10 mg versus separate tablets in healthy subjects.","authors":"Jisoo Song, Sungyeun Bae, Kyung-Sang Yu, SeungHwan Lee","doi":"10.12793/tcp.2025.33.e5","DOIUrl":"https://doi.org/10.12793/tcp.2025.33.e5","url":null,"abstract":"<p><p>The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are well-established treatment options for dyslipidemia. For patients not meeting low-density lipoprotein cholesterol targets with monotherapy, combination therapy with another lipid-lowering agent including ezetimibe, is recommended. This study compared the pharmacokinetics (PKs) and safety of a fixed-dose combination (FDC) of atorvastatin/ezetimibe 5 mg/10 mg with the individual components in healthy Korean subjects. A randomized, open-label, single-dose, 2-treatment, 2-sequence, crossover study was conducted in 60 healthy subjects. An FDC of atorvastatin/ezetimibe 5 mg/10 mg or the corresponding individual components was administered in the first period, and the alternative in the second period after a 14-day washout. Serial blood samples were collected up to 72 hours post-dose to calculate PK parameters such as maximum plasma concentration (C_max) and the area under the plasma concentration-time curve to the last measurable concentration (AUC_last). The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the C_max and AUC_last for the atorvastatin and total ezetimibe were estimated compared to the individual components. Adverse events (AEs) and other safety variables were monitored to evaluate safety and tolerability profile. Sixty subjects were enrolled and 58 subjects completed the study. For atorvastatin, the GMRs (90% CIs) for C_max and AUC_last were 1.18 (1.04-1.33) and 1.04 (1.00-1.08), respectively, and the corresponding values were 1.37 (1.26-1.50) and 0.98 (0.93-1.03) for total ezetimibe. No clinically significant treatment-emergent AEs were observed with either formulations. The FDC of atorvastatin/ezetimibe 5 mg/10 mg was safe and showed similar exposure to those of the individual components.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT05202405.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"33 1","pages":"40-49"},"PeriodicalIF":1.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11976153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical development of oral semaglutide for the treatment of type 2 diabetes mellitus: focusing on early phase clinical trials.","authors":"Heejae Won, Joo-Youn Cho, SeungHwan Lee","doi":"10.12793/tcp.2025.33.e3","DOIUrl":"https://doi.org/10.12793/tcp.2025.33.e3","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder often associated with obesity and elevated cardiovascular risks. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become integral to T2DM management due to their clinical benefits of glucose regulation and weight loss. However, their subcutaneous administration presents challenges to patient adherence, limiting their widespread use. Oral semaglutide (Rybelsus^®), the first oral GLP-1 RA approved for T2DM, addresses these challenges through an innovative co-formulation with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which enhances gastric absorption and stability. This review provides a comprehensive overview of the clinical development of oral semaglutide, with a focus on early-phase trials. Phase 1 studies investigated pharmacokinetics, pharmacodynamics, safety, and dose-response relationships, demonstrating a dose-dependent reduction in hemoglobin A_1c (HbA_1c) and body weight with an acceptable safety profile. Additionally, pharmacological evaluations of interactions with food, dosing condition, disease states, and concomitant medications supported the determination of an optimal dosing regimen for further clinical studies. Phase 2 dose-finding trials confirmed significant HbA_1c and weight reductions comparable to subcutaneous semaglutide, which guided dose selection for phase 3 trials. Phase 3 trials, including the Peptide InnOvatioN for Early diabEtes tReatment program, demonstrated significant reductions in HbA_1c, weight loss, and cardiovascular safety, positioning oral semaglutide as a transformative option in diabetes care. The study highlights comprehensive clinical strategies and provides an insight into the future development of oral GLP-1 RAs and other oral peptide drugs.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"33 1","pages":"1-9"},"PeriodicalIF":1.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11976150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of first-in-human dose for new composition bee venom based on allometric scaling and pharmacokinetic modeling approach.","authors":"Soon Uk Chae, Jee Sun Min, Seong Jun Jo, Chae Bin Lee, Jinha Park, Soo Hyeon Bae, Soo Kyung Bae","doi":"10.12793/tcp.2025.33.e4","DOIUrl":"https://doi.org/10.12793/tcp.2025.33.e4","url":null,"abstract":"<p><p>Bee venom is a traditional remedy used to treat conditions related to the nervous and musculoskeletal systems, as well as autoimmune diseases. Recently, we developed a new composition bee venom (NCBV), a fortified content of bee venom phospholipase A2 (bvPLA2), which may be effective in the treatment of Alzheimer's disease. NCBV is currently preparing to conduct a phase 1 clinical trial, and this study aimed to predict the first-in-human (FIH) dose using a mechanistic approach. First, animal pharmacokinetic (PK) studies from three different species were explored and integrated to build a PK model using nonlinear mixed-effect modeling. The final models were described by two-compartment model with first order absorption and elimination, and were used to define the PK parameters for each species. To predict human PK parameters, simple, brain weight (BrW) or maximum lifespan potential (MLP) incorporated allometric scaling approaches were used, with the BrW method showing the highest correlation (R² = 0.974). The initial FIH dose was back-calculated based on the area under the concentration-time curve of 0.397 μg·h/mL after the injection of an efficacious dose of 0.1 mg/kg in mice using the developed PK model. The predicted initial doses for a 70 kg human were 5.5, 1.3, and 3.5 mg, when using the simple, BrW, and MLP incorporated model, respectively. A subcutaneous FIH dose of 1.3 mg NCBV was ultimately recommended for a 70-kg human. Based on the no observed adverse effect level, the suggested FIH dose ranges for NCBV are 0.1 to 3 mg, which correspond with our proposed dose.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"33 1","pages":"27-39"},"PeriodicalIF":1.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11976151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research on unintroduced new drugs in South Korea from 2011 to 2020: approaches to prioritization and strategy.","authors":"Hyewon Jeon, Sang-In Park, Sang-Won Lee, Tae-Eun Kim, Kwang-Hee Shin, Ildae Song, Hyewon Chung, Byoungjun Bae, Sonu Baik, Namyi Gu","doi":"10.12793/tcp.2024.32.e19","DOIUrl":"10.12793/tcp.2024.32.e19","url":null,"abstract":"<p><p>In recent years, with the experience of the COVID-19 pandemic, countries around the world have realized that improving patient access to new medicines can have a significant impact on public health and economic stability. The aim of this study was to identify new drugs that are urgently needed among those not yet available in South Korea from 2011 to 2020, and to develop strategies to improve access by analyzing the causes of delay. Through a 3-step screening process that included a literature review of new drugs, surveys of domestic clinicians and academics, and consideration of expedited review status by regulatory authorities, 34 out of 244 unreleased new drugs were prioritized for rapid introduction. Reasons for drug delays were investigated through inquiries to the marketing authorization holders of the prioritized drugs and interviews with experts on new drug introductions. Key considerations for market entry include exemption from bridging clinical trials, reimbursement listing, and maximum reimbursement price. For foreign developers without domestic subsidiaries, providing systematic support-such as clear information on Korea's regulatory standards and facilitating reliable partnership matching-could improve access to priority unintroduced new drugs. Based on the results of this study, we propose strategies to facilitate the introduction of priority new drugs in South Korea.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"32 4","pages":"187-197"},"PeriodicalIF":1.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PMDA initiatives to enhance drug development via multi-regional clinical trials.","authors":"Yasuto Otsubo","doi":"10.12793/tcp.2024.32.e16","DOIUrl":"10.12793/tcp.2024.32.e16","url":null,"abstract":"","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"32 4","pages":"173-176"},"PeriodicalIF":1.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analyzing collaborations in clinical trials in Korea using association rule mining.","authors":"Ki Young Huh, Ildae Song","doi":"10.12793/tcp.2024.32.e17","DOIUrl":"10.12793/tcp.2024.32.e17","url":null,"abstract":"<p><p>Identifying how trial sites collaborate is essential for multicenter trials. The ways in which collaboration among trial sites is established can vary according to study phase and clinical trial domains. In this study, we employed association rule mining to reveal trial collaboration. We used trial approval data provided by the Ministry of Food and Drug Safety in Korea and organized the trial sites. We collected trial information from 2012 to 2023 and categorized the trials according to study phase and clinical trial domain. We performed association rule mining based on study phase and clinical trial domain. We identified 209 valid trial sites and analyzed 11,107 clinical trials conducted during this period. By study phase, phase 1 trials accounted for the largest number (5,451), followed by phase 3 (2,492), others (1,826), and phase 2 (1,338). We found that phase 1 clinical trials had the highest lift metrics. The mean lift for phase 1 trials was 5.40, which was significantly greater than that of phase 2 (1.68) and phase 3 trials (1.72). Additionally, the network structure for trial collaboration in phase 1 trials was highly condensed, with several trial sites located in Seoul and Gyeonggi-do. Different trial collaboration characteristics were noted among clinical trial domains, with mean and variability of the lift metrics for pediatrics being the highest. In conclusion, association rule mining can identify collaborations among trial sites. Collaboration in phase 1 trials is relatively more exclusive than in other phases, and aspects of collaboration differ among clinical trial domains.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"32 4","pages":"177-186"},"PeriodicalIF":1.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiotoxicity evaluation of two-drug fixed-dose combination therapy under CiPA: a computational study.","authors":"Ali Ikhsanul Qauli, Aroli Marcellinus, Frederique Jos Vanheusden, Ki Moo Lim","doi":"10.12793/tcp.2024.32.e20","DOIUrl":"10.12793/tcp.2024.32.e20","url":null,"abstract":"<p><p>The Comprehensive <i>In Vitro</i> Proarrhythmia Assay (CiPA) evaluates drug-induced torsade de pointes (TdP) risk, with qNet commonly used to classify drugs into low-, intermediate-, and high-risk categories. While most studies focus on single-drug effects, 2-drug fixed-dose combination (FDC) therapy is widely used for cardiovascular disease management. We aimed to develop the CiPA-based methodology to predict adverse effects of FDC therapy. A human ventricular cell model was stimulated under the effects of various drug combinations from twelve well-characterized compounds suggested by CiPA at 1 to 4 maximum plasma concentration, and the qNet_avg biomarker as a function of the ratio of two drugs was used to evaluate the TdP risk of combined compounds. Results showed that high-risk and intermediate-risk drug combinations often yielded lower qNet_avg than individual drugs, suggesting increased TdP risk. Conversely, combinations involving low-risk drugs tended to reduce TdP risk by raising qNet_avg above individual drug levels. Also, we found that the interplay of some major ionic channels caused variations on qNet_avg. These findings highlight the importance of evaluating FDC cardiotoxicity to predict risks that may not appear in single-drug analysis.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"32 4","pages":"198-215"},"PeriodicalIF":1.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative pharmacokinetics study of two tablet formulations of delpazolid, a novel oxazolidinone class antibiotic.","authors":"JaeEun Koh, Juyoung Khwarg, Young Lag Cho, Kyung-Sang Yu, Jae-Yong Chung","doi":"10.12793/tcp.2024.32.e18","DOIUrl":"10.12793/tcp.2024.32.e18","url":null,"abstract":"<p><p>Delpazolid is an oxazolidinone-class antibiotic under development for treating diseases caused by antimicrobial-resistant gram-positive bacteria. This study compared the pharmacokinetics (PK) and safety of two formulations of delpazolid 400 mg with distinct excipient compositions: Batch No. 3183817R (test drug) and Batch No. 1650006 (reference drug). A randomized, open-label, single-dose, two-way crossover study was conducted. The participants received a single oral dose of delpazolid 400 mg (test or reference) in each period, with serial blood samples collected up to 12 hours post-dose. The PK parameters of delpazolid were calculated using a noncompartmental method. The geometric mean ratios (GMRs) and its 90% confidence intervals (CIs) of the test drug to the reference drug were estimated for the maximum plasma concentration (C_max) and area under the plasma concentration-time curve from time zero to the last observation (AUC_last). Safety assessments were also conducted. Twenty-four participants completed the study as planned. The PK profiles of delpazolid were similar between the test and reference drugs. The GMRs (90% CIs) of the test to the reference for C_max and AUC_last were 1.1265 (0.8666-1.4644) and 1.0290 (0.9402-1.1261), respectively. The result of AUC_last met the bioequivalence criteria (0.8-1.25), but the 90% CI for C_max exceeded the upper limit of 1.25. Both drugs were safe and well tolerated. The two different delpazolid formulations showed comparable PK and safety profiles, indicating that the test drug is an appropriate alternative to the reference drug.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT04939779.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"32 4","pages":"216-224"},"PeriodicalIF":1.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}