Translational and Clinical Pharmacology最新文献

{"title":"Exploratory comparative pharmacokinetic study of a fixed-dose combination of telmisartan/amlodipine/chlorthalidone: half-dose (20/2.5/6.25 mg) versus conventional dose (40/5/12.5 mg).","authors":"Kyungrin Chang, Heejae Won, Taewon Lee, Soonkeun Kwon, Seung Hwan Lee, Joo-Youn Cho, Kyung-Sang Yu","doi":"10.12793/tcp.2026.34.e5","DOIUrl":"https://doi.org/10.12793/tcp.2026.34.e5","url":null,"abstract":"<p><p>Low-dose combination therapies are recommended when monotherapy fails to control hypertension. This exploratory study aimed to compare the pharmacokinetics (PK) of 2 fixed-dose combinations (FDCs) of telmisartan, amlodipine, and chlorthalidone: half-dose test FDC (20/2.5/6.25 mg) and a conventional-dose reference FDC (40/5/12.5 mg). A randomized, open-label, single-dose, parallel-group study was conducted in healthy participants. Each participant received a single oral dose of either the test or reference FDC. Serial blood samples for telmisartan, amlodipine, and chlorthalidone were collected up to 72 hours post-dose, and PK parameters were calculated using noncompartmental analysis. The mean maximum plasma concentrations (C_max) of telmisartan, amlodipine, and chlorthalidone were 41.34 and 155.75 μg/L, 1.74 and 4.42 μg/L, and 39.36 and 104.86 μg/L for the test and reference FDCs, respectively. The mean area under the concentration-time curves to the last measurable time point (AUC_last) were 659.93 and 1,673.51 h·μg/L for telmisartan, 57.98 and 128.75 h·μg/L for amlodipine, and 831.73 and 1,826.86 h·μg/L for chlorthalidone. The test FDC demonstrated systemic exposure levels ranging from 0.27- to 0.39-fold for telmisartan, 0.39- to 0.44-fold for amlodipine, and 0.38- to 0.46-fold for chlorthalidone, compared to the reference FDC. In conclusion, the PK profiles of the half-dose test FDC were consistent with the known characteristics of the individual components. These provide the first PK data for this half-dose test FDC and may support its potential as an alternative treatment option for hypertension. However, as this was an exploratory study, the results should be interpreted with caution.</p><p><strong>Trial registration: </strong>Clinical Research Information Service Identifier: KCT0010166.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 1","pages":"45-57"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147676994","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":"Pioneering pharmacometrics practice in Korea: an eight-year retrospective analysis of 192 projects from the first dedicated service organization (2016-2024).","authors":"So Jin Lee, Soo Hyeon Bae, Jinha Park, Yunjung Hong, Yearin Jun, Seunghoon Han, Dong-Seok Yim","doi":"10.12793/tcp.2026.34.e4","DOIUrl":"https://doi.org/10.12793/tcp.2026.34.e4","url":null,"abstract":"<p><p>Pharmacometrics has become a pivotal component of drug development and regulatory science in Korea, evolving from traditional pharmacokinetic (PK)/pharmacodynamic (PD) modeling to advanced approaches such as physiologically based pharmacokinetic (PBPK) modeling and quantitative systems pharmacology (QSP). This study reviews 192 pharmacometrics projects conducted between 2016 and 2024 by Korea's first pharmacometrics service company, covering diverse modalities, indications, and development stages. Key applications included first-in-human dose prediction, clinical trial design, and patient population-specific PK/PD modeling, with systematic tracking of regulatory outcomes and publications. While oncology remained the dominant therapeutic area, recent projects expanded into gene therapy, GLP-1 agonists, pediatric orphan indications, and advanced biologics including antibody-drug conjugates, bispecific antibodies, and engineered fusion proteins-using PBPK and semi-mechanistic models. These case-driven analyses highlight the growing regulatory impact and strategic value of pharmacometrics. As the field moves into a new era shaped by artificial intelligence/machine learning integration and Food and Drug Administration-driven new approach methodologies initiatives, this review not only reflects on past practices and achievements but also provides strategic perspectives to guide the future direction of pharmacometrics in Korea.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 1","pages":"15-34"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147676375","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 pH factor: unraveling drug-drug interactions in protein kinase inhibitors through the regulatory lens.","authors":"Simona Stankeviciute, Ariel Tsai, Noha Rayad, Matthias Kruse","doi":"10.12793/tcp.2026.34.e6","DOIUrl":"https://doi.org/10.12793/tcp.2026.34.e6","url":null,"abstract":"<p><p>Drug-drug interactions (DDIs) are a significant concern in clinical practice, DDIs might be relevant when drugs with pH-dependent solubility are co-administered with gastric acid-reducing agents (ARAs) such as histamine, H2-receptor antagonists and proton pump inhibitors. One class prone to such DDI at the absorption phase are the weakly basic protein kinase inhibitors (PKIs). The aim of this work is to review recent Food & Drug Administration (FDA) and European Medicines Agency (EMA) submissions for PKIs and evaluate the various approaches by drug developers to characterize pH-dependent DDI liability potentially affecting efficacy in this class of drugs and assess how this impacts the labelling. For this purpose, 32 FDA New Drug Applications (NDAs) and 25 EMA Market Authorization Applications of PKIs in the last 5 years (2019 through 2024) were reviewed More than two-thirds of the submissions included a dedicated clinical DDI studies with an ARA, which remains the most frequent approach to evaluating gastric pH-dependent DDIs among the PKIs investigated, albeit model-informed drug development approaches are also attempted by applicants in about 20% of the submissions. In cases where no clinical DDI study was submitted and alternative approaches taken, this was accepted by the approving agencies. Only the complete absence of data on the DDI potential triggered the request to provide the information post-marketing. A risk-based approach, considering the drug's properties and patient population, is crucial for determining the need for a clinical DDI study and should be discussed with the agencies during drug development.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 1","pages":"1-14"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147676570","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":"Erratum: A review of clinical pharmacology considerations in antibody-drug conjugates approved by the US Food and Drug Administration between 2000 and 2025.","authors":"Seoyoung Koo, Chae Yeon Kim, Jeong Hyeon Lim, Eunyoung Lee, In Young Kim, Young G Shin, Hanlim Moon","doi":"10.12793/tcp.2026.34.e3","DOIUrl":"https://doi.org/10.12793/tcp.2026.34.e3","url":null,"abstract":"<p><p>[This corrects the article on p. 197 in vol. 33, PMID: 41551730.].</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 1","pages":"69"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147676991","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":"Incidence and sex-related risk factors of linezolid-associated adverse drug reactions identified through electronic health records.","authors":"Seunghwan Baek, JungJin Oh, SiYeon Yoon, Seonghae Yoon, Jae-Yong Chung","doi":"10.12793/tcp.2026.34.e1","DOIUrl":"https://doi.org/10.12793/tcp.2026.34.e1","url":null,"abstract":"<p><p>Linezolid is an oxazolidinone antibiotic widely used to treat gram-positive infections and is associated with frequent adverse drug reactions (ADRs). Nevertheless, comprehensive evaluations of the incidence and risk factors of linezolid-related ADRs remain limited, with substantial variability across studies. This study aimed to evaluate the incidence of linezolid-associated ADRs and identify potential risk factors. A retrospective analysis was conducted using the Clinical Data Warehouse of Seoul National University Bundang Hospital (2003-2025). Among patients receiving at least one dose of linezolid, thrombocytopenia, neutropenia, anemia, leukopenia, and lactic acidosis were identified as ADRs. Kaplan-Meier analysis assessed cumulative incidence, and univariable and multivariable logistic regression were performed to identify risk factors. Among 1,198 patients, the cumulative incidences of thrombocytopenia, anemia, leukopenia, neutropenia, and lactic acidosis within three months after linezolid treatment initiation were 44.7%, 57.3%, 45.8%, 29.9%, and 27.5%, respectively. Concomitant use of trimethoprim-sulfamethoxazole was associated with anemia, while female sex and receipt of fresh frozen plasma transfusion were associated with lactic acidosis. Red blood cell transfusion was associated with an increased incidence of thrombocytopenia. This study demonstrated a higher incidence of linezolid-associated ADRs than previously reported in registration clinical trials. While several concomitant medications and clinical factors were identified as potential risk factors, associations involving transfusion-related variables should be interpreted cautiously, as they likely reflect underlying clinical vulnerability rather than a direct causal effect. These findings emphasize the importance of ADR monitoring during linezolid therapy and further research on the underlying mechanisms of linezolid-associated toxicity.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 1","pages":"35-44"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147677036","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 of a candesartan/amlodipine/atorvastatin fixed-dose combination 8 mg/5 mg/10 mg versus separate tablets in healthy subjects: a partial replicated crossover study.","authors":"So-Yeon Kim, Yong-Geun Kwak, Min-Gul Kim, Seol Ju Moon","doi":"10.12793/tcp.2026.34.e2","DOIUrl":"https://doi.org/10.12793/tcp.2026.34.e2","url":null,"abstract":"<p><p>Management of hypertension and hyperlipidemia is important to reduce the risk of cardiovascular disease, and a fixed-dose combination (FDC) of antihypertensive and lipid-lowering drugs is expected to reduce the pill burden and increase patient compliance. The aim of this study was to compare the pharmacokinetics (PKs) of candesartan, amlodipine, and atorvastatin FDC versus separate tablets. A randomized, open-label, single-dose, 2-treatment, 3-sequence, 3-period, partial replicated crossover study was conducted in healthy subjects. A total of 51 subjects were randomized into 1 of 3 sequences and received a single dose of either an FDC or separate tablets of candesartan 8 mg, amlodipine 5 mg, and atorvastatin 10 mg, with a 14-day washout period in between. Plasma samples were collected up to 72 hours after dosing. Plasma concentrations of candesartan, amlodipine and atorvastatin were assayed using a validated LC-MS/MS method, and PK parameters were determined by noncompartmental analysis. As a result, 43 subjects were included in PK analysis for candesartan, atorvastatin, and 42 subjects were included in PK analysis for amlodipine. The geometric mean ratios (90% confidence intervals) of the area under the plasma concentration-time curve from time zero to the last sampling time and maximum plasma concentration were 0.9637 (0.9192-1.0104) and 0.9360 (0.8885-0.9861) for candesartan, 0.9694 (0.9417-0.9978) and 0.9930 (0.9575-1.0299) for amlodipine, and 1.0350 (0.9891-1.0831) and 1.0658 (0.9370-1.2123) for atorvastatin, respectively. This study suggested that the FDC formulation of candesartan, amlodipine, and atorvastatin showed PK equivalence compared to separate tablets.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT04611932.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"34 1","pages":"58-68"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147677045","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":"Acid-suppressive effect of tegoprazan 12.5 mg BID: a phase 1 comparative study with tegoprazan 25 mg QD and famotidine 20 mg BID.","authors":"Ho-Sook Kim, Young-Kyung Choi, Minkyung Oh, Yong-Soon Cho, Jong-Lyul Ghim","doi":"10.12793/tcp.2025.33.e18","DOIUrl":"10.12793/tcp.2025.33.e18","url":null,"abstract":"<p><p>Tegoprazan is a potassium-competitive acid blocker that directly inhibits the gastric proton pump, whereas famotidine is a histamine-2 receptor antagonist that indirectly suppresses acid secretion with known tolerance to repeated dosing. This phase 1 study evaluated the pharmacokinetics, pharmacodynamics, and safety of tegoprazan 12.5 mg twice daily (BID) compared with tegoprazan 25 mg once daily (QD) and famotidine 20 mg BID in healthy subjects. Thirty-six participants were randomized to one of the 3 regimens for 14 days. In pharmacokinetic analysis, tegoprazan 12.5 mg BID showed lower steady-state Cmax but higher trough concentrations than 25 mg QD, while overall systemic exposure was comparable, with a Day 14 geometric mean ratio for area under the concentration-time curve over 24 hours of 1.08 (90% confidence interval, 0.85-1.36). Pharmacodynamic assessment using 24-hour intragastric pH monitoring demonstrated superior and sustained acid suppression with tegoprazan 12.5 mg BID. On Day 14, the percentage of time with intragastric pH > 3 over 24 hours was 75.1% with tegoprazan 12.5 mg BID, compared with 55.4% with 25 mg QD and 40.3% with famotidine. Both tegoprazan regimens maintained relatively consistent acid suppression from Day 1 to Day 14 (71.8% to 75.1% and 56.4% to 55.4%), whereas famotidine showed a decline (65.3% to 40.3%). Similar time-dependent patterns were observed during the nighttime period and in the supine position. Tegoprazan 12.5 mg BID was well tolerated, with no adverse events reported in this group. These findings suggest that low-dose tegoprazan 12.5 mg BID provides safe and sustained acid suppression.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"33 4","pages":"238-251"},"PeriodicalIF":1.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12806658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145999052","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 effectiveness of long-term anti-obesity medications in routine clinical practice: a retrospective cohort study using real-world data.","authors":"Chul-Gyu Kim, Jung-Min Koh, Kyun-Seop Bae","doi":"10.12793/tcp.2025.33.e20","DOIUrl":"10.12793/tcp.2025.33.e20","url":null,"abstract":"<p><p>Orlistat, phentermine/topiramate, and liraglutide are widely used obesity pharmacotherapies, but comparative data from Asian real-world settings remain limited. We compared their effects on body weight, glycemic control, and persistence. We performed a retrospective cohort study using electronic health records from a tertiary hospital in Korea. Adults prescribed orlistat, phentermine/topiramate, or liraglutide between 2018 and 2025 were included. The primary endpoint was percentage weight change at 6 months. Secondary endpoints were the proportions achieving ≥5% and ≥10% weight loss, weight change at 3, 6, and 12 months, change in HbA1c, and 12-month treatment persistence. We applied multivariable linear and logistic regression, linear mixed-effects models, propensity score-weighted models, and Kaplan-Meier and restricted mean survival time (RMST) methods. Among 1,910 treatment episodes, 505 involved orlistat, 777 phentermine/topiramate, and 628 liraglutide. Phentermine/topiramate showed greater mean percentage weight loss at 6 months than orlistat (adjusted difference, -1.59 percentage points; <i>p</i> < 0.001), whereas liraglutide produced similar weight loss to orlistat. The odds of achieving ≥5% weight loss were higher with phentermine/topiramate than with orlistat (adjusted odds ratio, 2.21), while liraglutide showed a smaller effect. Liraglutide tended to reduce HbA1c more than orlistat, but this difference was attenuated after propensity score weighting. Twelve-month treatment persistence and RMST were lower with liraglutide than with the oral agents. In this real-world cohort, phentermine/topiramate achieved the most pronounced and sustained weight loss. Liraglutide and orlistat produced similar overall weight reduction, but liraglutide showed lower long-term persistence.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"33 4","pages":"224-237"},"PeriodicalIF":1.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12806651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998565","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":"A review of clinical pharmacology considerations in antibody-drug conjugates approved by the US Food and Drug Administration between 2000 and 2025.","authors":"Seoyoung Koo, Chae Yeon Kim, Jeong-Hyeon Lim, Eunyoung Lee, In Young Kim, Young G Shin, Hanlim Moon","doi":"10.12793/tcp.2025.33.e21","DOIUrl":"10.12793/tcp.2025.33.e21","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) represent a promising class of anticancer therapies with rapidly expanding development. However, regulatory approval remains complex due to their unique pharmacological properties. We systematically analyzed U.S. Food and Drug Administration (FDA)'s clinical pharmacology considerations across all approved ADCs to identify consistent regulatory patterns and inform future development strategies. We comprehensively reviewed 13 FDA-approved ADCs as of March 2025, examining clinical pharmacology and/or multidisciplinary reviews from Drugs@FDA. Six key parameters from the <i>FDA's Clinical Pharmacology Considerations for Antibody</i>-<i>Drug Conjugates: Guidance for Industry (2024)</i> were evaluated: bioanalytical methods, exposure-response relationships, intrinsic factors, extrinsic factors, QTc prolongation, and immunogenicity. For each parameter, we assessed: 1) submission completeness, 2) FDA's assessment, and 3) whether they led to regulatory actions such as post-marketing requirements/commitments (PMRs/PMCs). All 6 clinical pharmacology considerations were consistently applied throughout ADC approval history, well before the issuance of formal guidance. The FDA maintained particularly rigorous standards across a few critical domains. Exposure-response interpretation considering critical safety issues, intrinsic factor analyses-particularly hepatic impairment and racial variations-and validated immunogenicity assays including the neutralizing antibody emerged as primary scrutiny points. These factors repeatedly triggered similar PMRs/PMCs across multiple ADCs, underscoring their regulatory significance. Core clinical pharmacology parameters consistently shape FDA assessments of ADCs. Proactive alignment with regulatory expectations can streamline development, mitigate potential delays, and reduce post-marketing obligations. Our historical analysis provides strategic insights that may support clinical investigators for optimizing future ADC development.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"33 4","pages":"197-211"},"PeriodicalIF":1.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12806659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145999071","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":"Sex differences in efficacy/safety of anti-amyloid-beta monoclonal antibodies for the treatment of Alzheimer's disease.","authors":"SoHyeon Lim, Hyun-Woo Lee, Siyeon Yoon, Ji Won Han, Jae-Yong Chung, Seonghae Yoon","doi":"10.12793/tcp.2025.33.e19","DOIUrl":"10.12793/tcp.2025.33.e19","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common cause of dementia. AD exhibits notable sex-related disparities in prevalence, progression, and treatment response. With the recent approval of anti-amyloid-beta monoclonal antibodies-aducanumab, lecanemab, and donanemab-understanding sex differences in their clinical effects has become increasingly relevant. This review article investigates sex differences in the pharmacokinetics, efficacy, and safety of aducanumab, lecanemab, and donanemab and discusses the possible mechanism underlying the observed differences. Although sex-specific analyses were largely underreported in clinical trials, population pharmacokinetic models identified sex as a covariate affecting clearance and volume of distribution for aducanumab and lecanemab and higher exposure to lecanemab was predicted for females. Subgroup analyses of phase 3 trials revealed that males tended to experience greater benefit from aducanumab and lecanemab, whereas females showed better response to donanemab. The overall incidence of adverse events, including amyloid-related imaging abnormalities, did not show significant differences between sexes. Potential mechanisms underlying these differences include sex-related variations in blood-brain barrier permeability, apolipoprotein E4-associated neuroinflammatory responses, and baseline disease characteristics. These findings underscore the need for future AD clinical trials to incorporate sex-based analyses and to consider sex as a key factor in optimizing treatment strategies.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"33 4","pages":"212-223"},"PeriodicalIF":1.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12806652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998550","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}