Cts-Clinical and Translational Science最新文献

{"title":"Serum creatine kinase elevation following tyrosine kinase inhibitor treatment in cancer patients: Symptoms, mechanism, and clinical management","authors":"Hang Zhang,&nbsp;Kenneth K. W. To","doi":"10.1111/cts.70053","DOIUrl":"10.1111/cts.70053","url":null,"abstract":"<p>Molecular targeted tyrosine kinase inhibitors (TKIs) have produced unprecedented treatment response in cancer therapy for patients harboring specific oncogenic mutations. While the TKIs are mostly well tolerated, they were reported to increase serum levels of creatine kinase (CK) and cause muscle metabolism-related toxicity. CK is an essential enzyme involved in cellular energy metabolism and muscle function. Elevated serum CK levels can arise from both physiological and pathological factors, as well as triggered by specific drug classes. The incidence of serum CK elevation induced by a few approved TKIs (brigatinib, binimetinib, cobimetinib-vemurafenib combination [Food and Drug Administration, United States]; aumolertinib, and sunvozertinib [only approved by National Medical Products Administration, China]) were over 35%. CK elevation-related symptoms include myopathy, myositis, inclusion body myositis (IBM), cardiotoxicity, rhabdomyolysis, rash, and acneiform dermatitis. High-level or severe symptomatic CK elevation may necessitate dose reduction and indirectly dampen TKI efficacy. This review presents an updated summary about the prevalence rate and recent research about mechanisms leading to TKI-induced serum CK elevation in cancer patients. The utility of monitoring serum CK levels for predicting TKI-induced adverse effects and their management will also be discussed.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Practical guide to SHAP analysis: Explaining supervised machine learning model predictions in drug development","authors":"Ana Victoria Ponce-Bobadilla,&nbsp;Vanessa Schmitt,&nbsp;Corinna S. Maier,&nbsp;Sven Mensing,&nbsp;Sven Stodtmann","doi":"10.1111/cts.70056","DOIUrl":"10.1111/cts.70056","url":null,"abstract":"<p>Despite increasing interest in using Artificial Intelligence (AI) and Machine Learning (ML) models for drug development, effectively interpreting their predictions remains a challenge, which limits their impact on clinical decisions. We address this issue by providing a practical guide to SHapley Additive exPlanations (SHAP), a popular feature-based interpretability method, which can be seamlessly integrated into supervised ML models to gain a deeper understanding of their predictions, thereby enhancing their transparency and trustworthiness. This tutorial focuses on the application of SHAP analysis to standard ML black-box models for regression and classification problems. We provide an overview of various visualization plots and their interpretation, available software for implementing SHAP, and highlight best practices, as well as special considerations, when dealing with binary endpoints and time-series models. To enhance the reader's understanding for the method, we also apply it to inherently explainable regression models. Finally, we discuss the limitations and ongoing advancements aimed at tackling the current drawbacks of the method.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thai pharmacogenomics database −2 (TPGxD-2) sequel to TPGxD-1, analyzing genetic variants in 26 non-VIPGx genes within the Thai population","authors":"Shobana John,&nbsp;Sommon Klumsathian,&nbsp;Paravee Own-eium,&nbsp;Angkana Charoenyingwattana,&nbsp;Jakris Eu-ahsunthornwattana,&nbsp;Thanyachai Sura,&nbsp;Donniphat Dejsuphong,&nbsp;Piyamitr Sritara,&nbsp;Prin Vathesatogkit,&nbsp;Nartthawee Thongchompoo,&nbsp;Wiphaporn Thabthimthong,&nbsp;Nuttinee Teerakulkittipong,&nbsp;Wasun Chantratita,&nbsp;Chonlaphat Sukasem","doi":"10.1111/cts.70019","DOIUrl":"10.1111/cts.70019","url":null,"abstract":"<p>Next-generation sequencing (NGS) has transformed pharmacogenomics (PGx), enabling thorough profiling of pharmacogenes using computational methods and advancing personalized medicine. The Thai Pharmacogenomic Database-2 (TPGxD-2) analyzed 948 whole genome sequences, primarily from the Electricity Generating Authority of Thailand (EGAT) cohort. This study is an extension of the previous Thai Pharmacogenomic Database (TPGxD-1) and specifically focused on 26 non-very important pharmacogenes (VIPGx) genes. Variant calling was conducted using Sentieon (version 201808.08) following GATK's best workflow practices. We then annotated variant call format (VCF) files using Golden Helix VarSeq 2.5.0. Star allele analysis was performed with Stargazer v2.0.2, which called star alleles for 22 of 26 non-VIPGx genes. The variant analysis revealed a total of 14,529 variants in 26 non-VIPGx genes, with <i>TBXAS1</i> had the highest number of variants (27%). Among the 14,529 variants, 2328 were novel (without rsID), with 87 identified as clinically relevant. We also found 56 known PGx variants among the known variants (<i>n</i> = 12,201), with <i>UGT2B7</i> (19.64%), <i>CYP1B1</i> (8.9%), <i>SLCO2B1</i> (8.9%), and <i>POR</i> (8.9%) being the most common. We reported a high frequency of intermediate metabolizers (IMs) in <i>CYP2F1</i> (34.6%) and <i>CYP4A11</i> (8.6%), and a high frequency of decreased functional alleles in <i>POR</i> (53.9%) and <i>SLCO1B3</i> (34.9%) genes. This study enhances our understanding of pharmacogenomic profiling of 26 non-VIPGx genes of notable clinical importance in the Thai population. However, further validation with additional computational and reference genotyping methods is necessary, and novel alleles identified in this study should undergo further orthogonal validation.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11502937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Absolute oral bioavailability of milvexian spray-dried dispersion formulation under fasted and fed conditions in healthy adult participants: An intravenous microtracer approach","authors":"Praneeth Jarugula,&nbsp;Sharif Soleman,&nbsp;Hyunmoon Back,&nbsp;Lisa J. Christopher,&nbsp;Dara Hawthorne,&nbsp;Ronald Aronson,&nbsp;Anh Bui,&nbsp;Angela Mirzac,&nbsp;Antoinette Ajavon-Hartmann,&nbsp;Vidya Perera,&nbsp;Bindu Murthy,&nbsp;Samira Merali","doi":"10.1111/cts.70058","DOIUrl":"10.1111/cts.70058","url":null,"abstract":"<p>Milvexian is an oral, small-molecule factor XIa inhibitor being developed to prevent thromboembolic events. This study assessed the absolute bioavailability (F) of milvexian following single doses of milvexian spray-dried dispersion (SDD) formulation under fed and fasted conditions, and milvexian solution, in healthy adult participants using an intravenous microtracer approach. This was a phase I, open-label, partially randomized, 4-sequence, 5-period crossover study. After fasting for ≥10 h, participants received milvexian 200-mg oral solution with a 100-μg ¹⁴C milvexian intravenous microtracer at the time of maximum observed plasma concentration. Following a 3-day washout, participants were randomized to 1 of 4 milvexian SDD treatment sequences in a crossover fashion: 25 mg fasted, 25 mg fed, 200 mg fasted, or 200 mg fed. Pharmacokinetic data were collected up to 72 h postdose. Seventeen participants were dosed, and 14 completed treatment. Under fasted conditions, milvexian F was ~100%, 58.2%, and 54.2% following administration of the oral solution, 25 mg SDD, and 200 mg SDD, respectively. Under fed conditions, milvexian F following 25 mg and 200 mg SDD was 44.3% and 75.6%, respectively. The milvexian SDD formulation at 25 mg and 200 mg resulted in similar F in a fasted state; under fed conditions, milvexian F decreased at 25 mg and increased at 200 mg. These findings clarify pharmacokinetic-related gaps observed in previous studies.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asia-inclusive drug development leveraging principles of ICH E5 and E17 guidelines: Case studies illustrating quantitative clinical pharmacology as a foundational enabler","authors":"Hong Lu,&nbsp;Lena Klopp-Schulze,&nbsp;Jatinder Kaur Mukker,&nbsp;Dandan Li,&nbsp;Yoshihiro Kuroki,&nbsp;Jayaprakasam Bolleddula,&nbsp;Nadia Terranova,&nbsp;Kosalaram Goteti,&nbsp;Wei Gao,&nbsp;Rainer Strotmann,&nbsp;Jennifer Dong,&nbsp;Karthik Venkatakrishnan","doi":"10.1111/cts.70050","DOIUrl":"10.1111/cts.70050","url":null,"abstract":"<p>With the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guidelines in effect from 2018, the design of Asia-inclusive multiregional clinical trials (MRCTs) has been streamlined, thereby enabling efficient simultaneous global development. Furthermore, with the recent regulatory reforms in China and its drug administration joining the ICH as a full regulatory member, early participation of China in the global clinical development of novel investigational drugs is now feasible. This would also allow for inclusion of the region in the geographic footprint of pivotal MRCTs leveraging principles of the ICH E5 and E17. Herein, we describe recent case examples of model-informed Asia-inclusive global clinical development in the EMD Serono portfolio, as applied to the ataxia telangiectasia and Rad3-related inhibitors, tuvusertib and berzosertib (oncology), the toll-like receptor 7/8 antagonist, enpatoran (autoimmune diseases), the mesenchymal–epithelial transition factor inhibitor tepotinib (oncology), and the antimetabolite cladribine (neuroimmunological disease). Through these case studies, we illustrate pragmatic approaches to ethnic sensitivity assessments and the application of a model-informed drug development toolkit including population pharmacokinetic/pharmacodynamic modeling and pharmacometric disease progression modeling and simulation to enable early conduct of Asia-inclusive MRCTs. These examples demonstrate the value of a <i>Totality of Evidence</i> approach where every patient's data matter for de-risking ethnic sensitivity to inter-population variations in drug- and disease-related intrinsic and extrinsic factors, enabling inclusive global development strategies and timely evidence generation for characterizing benefit/risk of the proposed dosage in Asian populations.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11500040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mevalonate in blood and muscle: Response to atorvastatin treatment and the relationship to statin intolerance in patients with coronary heart disease","authors":"Trine Lauritzen,&nbsp;John Munkhaugen,&nbsp;Stein Bergan,&nbsp;Elise Sverre,&nbsp;Kari Peersen,&nbsp;Sofia Lindahl,&nbsp;Einar Husebye,&nbsp;Nils Tore Vethe","doi":"10.1111/cts.70025","DOIUrl":"10.1111/cts.70025","url":null,"abstract":"<p>Statin-associated muscle symptoms are frequently reported and often lead to discontinuation of statin therapy with an increased risk of cardiovascular events. In vitro studies suggest that statin-mediated inhibition of the mevalonate pathway leads to muscle cell toxicity. We aimed to determine the relationship between mevalonate, LDL-cholesterol, and atorvastatin metabolites in patients with coronary heart disease and self-perceived muscle side effects. Furthermore, we assessed the correlation between mevalonate in blood and muscle and the relationship to statin intolerance due to muscle symptoms. We used blood plasma from a randomized crossover trial (<i>n</i> = 70) and muscle biopsies and plasma from a subgroup in a subsequent open intervention study (<i>n</i> = 26). Both studies tested atorvastatin 40 mg/day. Seven patients did not tolerate ≥3 statins throughout the follow-up and were classified as statin-intolerant. Mevalonate in blood plasma decreased during atorvastatin treatment (median difference −38%, range −77% to 43%, <i>p</i> &lt; 0.001), whereas mevalonate in muscle tissue was not lowered (0.05%, range −47% to 145%). Mevalonate correlated poorly with LDL-cholesterol and atorvastatin metabolites (Spearman's rho −0.28 to 0.10). The statin-intolerant patients had a smaller reduction in circulating mevalonate compared with the tolerant patients; median difference −8.1 (−22 to 3.5) nmol/L versus −25 (−93 to 12) nmol/L, <i>p</i> = 0.028. A similar observation was made for LDL-cholesterol. Cutoffs based on these biomarkers classified &gt;50% correctly as tolerant. Inhibition of the mevalonate pathway does not appear to be the mechanism underlying statin intolerance in the present study. Further studies of mevalonate as a biomarker for statin tolerance are needed to clarify the potential.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidation of DPP-4 involvement in systemic distribution and renal reabsorption of linagliptin by PBPK modeling with a cluster Gauss–Newton method","authors":"Ryo Nakamura,&nbsp;Takashi Yoshikado,&nbsp;Yasunori Aoki,&nbsp;Yuichi Sugiyama,&nbsp;Koji Chiba","doi":"10.1111/cts.70047","DOIUrl":"10.1111/cts.70047","url":null,"abstract":"<p>The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (LNG) exhibits target-mediated drug disposition (TMDD) in clinical settings, characterized by saturable binding to plasma soluble DPP-4 (sDPP-4) and tissue transmembrane DPP-4 (tDPP-4). Previous studies have indicated that saturable renal reabsorption of LNG contributes to its nonlinear urinary excretion observed in humans and wild-type mice, but not in Dpp-4 knockout mice. To elucidate the mechanisms underlying these complex phenomena, including DPP-4-related renal reabsorption of LNG, we employed physiologically-based pharmacokinetic (PBPK) modeling combined with a cluster Gauss–Newton method (CGNM). The CGNM facilitated the exploration of parameters in rat and human PBPK models for LNG and the determination of parameter identifiability. Through PBPK–CGNM analysis using reported autoradiography data ([¹⁴C]-LNG) in wild-type and Dpp-4-deficient rats, DPP-4-specific distributions of LNG in various tissues were clearly differentiated from nonspecific parts. By fitting to human plasma concentrations and urinary and fecal excretions of LNG after intravenous and oral administrations, multiple unknown PBPK parameters were simultaneously estimated by the CGNM. Notably, the amount of tDPP-4 and the reabsorption clearance for LNG–DPP-4 complexes were identifiable, indicating their critical role in explaining the complex nonlinear pharmacokinetics of LNG. Compared with previous PBPK analyses, the CGNM allowed us to incorporate greater model complexity (e.g., consideration of tDPP-4 expressions and in vitro binding kinetics), ultimately resulting in a more accurate reproduction of LNG's TMDD. In conclusion, by considering LNG as a high-affinity probe for DPP-4, comprehensive PBPK–CGNM analyses suggested a dynamic whole-body distribution of DPP-4, including its involvement in the renal reabsorption of LNG.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On placental and lactational transfer of IgG-based therapeutic proteins – Current understanding and knowledge gaps from a clinical pharmacology perspective","authors":"Daphne Guinn,&nbsp;Katherine Kratz,&nbsp;Kristie Baisden,&nbsp;Sarah Ridge,&nbsp;Sonaly McClymont,&nbsp;Elimika Pfuma Fletcher,&nbsp;Tamara Johnson,&nbsp;Yow-Ming Wang","doi":"10.1111/cts.70049","DOIUrl":"10.1111/cts.70049","url":null,"abstract":"<p>Maternal medication use may expose the developing fetus through placental transfer or the infant through lactational transfer. Because pregnant and lactating individuals have been historically excluded from early drug development trials, there is often limited to no human data available to inform pharmacokinetics (PK) and safety in these populations at the time of drug approval. We describe the known mechanisms of placental or lactational transfer of IgG-based therapeutic proteins and use clinical examples to highlight the potential for fetal or infant exposure during pregnancy and lactation. Placental transfer of IgG-based therapeutic proteins may result in systemic exposure to the developing fetus. A lactational transfer may be associated with local gastrointestinal (GI) exposure in the infant and may also result in systemic exposure, although data are very limited as proteins have shown instability in the GI tract. Understanding of PK and pharmacodynamic (PD) effects of IgG-based therapeutic proteins in infants exposed in utero as well as the potential exposure through human milk and its clinical implications is critical for developing treatment strategies for pregnant or lactating individuals. We share the current knowledge gaps and considerations for future evaluations to inform PK, PD, and the safety of IgG-based therapeutic proteins for safe use during pregnancy and lactation. With the increasing use of IgG-based therapeutic proteins in treating chronic diseases during pregnancy and lactation, there is a need to improve the quantity and quality of data to inform the safe use in pregnant and lactating individuals.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Adult and pediatric relapsing multiple sclerosis phase II and phase III trial design and their primary endpoints: A systematic review”","authors":"","doi":"10.1111/cts.70052","DOIUrl":"10.1111/cts.70052","url":null,"abstract":"<p>Katsutoshi Hiramatsu, Hideki Maeda. Adult and pediatric relapsing multiple sclerosis phase II and phase III trial design and their primary end points: A systematic review. <i>Clin Transl Sci</i>. 2024;17:e13794.</p><p>We apologize for this error.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics, pharmacodynamics, and safety of izuforant, an H4R inhibitor, in healthy subjects: A phase I single and multiple ascending dose study","authors":"Byung Hak Jin,&nbsp;Taegon Hong,&nbsp;Byung Won Yoo,&nbsp;Choon Ok Kim,&nbsp;Dasohm Kim,&nbsp;Youn Nam Kim,&nbsp;Min Soo Park","doi":"10.1111/cts.70032","DOIUrl":"10.1111/cts.70032","url":null,"abstract":"<p>Izuforant is a selective, and potent histamine H4 receptor (H4R) antagonist developed to treat atopic dermatitis (AD). There is an unmet medical need for therapeutic agents to control inflammation and pruritus. Izuforant is a strong candidate for this task based on the findings of non-clinical studies showing that inhibition of the histamine-mediated signaling pathway via H4R by izuforant results in decreased pruritus and inflammation. This study aimed to evaluate the clinical pharmacokinetic (PK) and pharmacodynamic (PD) profiles of izuforant. Dose-block-randomized, double-blind, placebo-controlled, single- and multiple ascending dose studies were conducted in 64 healthy volunteers. For the single ascending dose (SAD) study, 10–600 mg izuforant was administered to the designated groups. For the multiple ascending dose (MAD) study, 100–400 mg izuforant was administered to three groups. The clinical pharmacokinetic (PK) profile of izuforant was evaluated using plasma and urine concentrations. Blood sampling for the PD assay, which measured imetit-induced eosinophil shape changes (ESC), was also conducted. A one-compartment PK model described the distribution and elimination profiles of izuforant. An imetit-induced ESC inhibition test was established and validated for PD evaluation as a measure of the H4R antagonistic effect. ESC inhibition was observed even at doses as low as 10 mg; however, this inhibition became stronger and lasted longer as the dose increased. All izuforant doses were well tolerated, and no discontinuations due to adverse events (AE) or deaths were reported.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}