Cts-Clinical and Translational Science最新文献

{"title":"Prevalence of OATP1B-Mediated Drug–Drug Interactions in an Academic Medical Center","authors":"Mathilde Bories,&nbsp;David Malnoë,&nbsp;Pascal Le Corre","doi":"10.1111/cts.70260","DOIUrl":"https://doi.org/10.1111/cts.70260","url":null,"abstract":"<p>OATP1B is a key transporter involved in hepatic drug uptake, where its inhibition can significantly increase plasma drug levels, leading to potential adverse effects. This retrospective study aimed to determine the prevalence of potential drug–drug interactions (pDDIs) mediated by the hepatic transporter OATP1B1/3 in a cohort of 44,877 patients hospitalized at Rennes Academic Medical Center, using data from the Clinical Data Warehouse. We analyzed prescription rates of OATP1B substrates and inhibitors and estimated the prevalence of pDDIs, assessed the consistency of pDDI identification across different drug interaction databases, and performed a literature review of identified OATP1B-based pDDIs. The identification of pDDIs across different drug databases showed inconsistencies, with limited overlap and variability in reported interactions. Among hospitalized patients, 6954 (15.5%) received OATP1B substrates, while 408 (0.9%) received inhibitors, leading to 106 pDDIs observed in 99 patients (0.2%). The pDDI rate varied significantly depending on the inhibitor used, reaching up to 39.1% in patients treated with ciclosporin. Statins accounted for a large proportion of pDDIs, emphasizing the potential risks, especially in multidrug regimens. Commonly involved inhibitors included FDA drugs such as ciclosporin, clarithromycin, and rifampicin. The clinical relevance of these interactions remains uncertain due to the limited availability of supporting evidence and the restricted list of well-characterized OATP1B substrates and inhibitors. This study highlights the complexity of OATP1B-mediated pDDIs and the need for increased clinical awareness and further research to improve the detection and characterization of such pDDIs, particularly for high-risk drugs with a narrow therapeutic index.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70260","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144213919","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":"Large-Scale Analysis of Age and Sex Effects on Corrected QT and JT Intervals: Insights From Hospital-Based Controls and Moxifloxacin-Treated Cases","authors":"Eunwoo Kim,&nbsp;Hyun Young Lee,&nbsp;Young-Min Ye,&nbsp;Anhye Kim","doi":"10.1111/cts.70263","DOIUrl":"https://doi.org/10.1111/cts.70263","url":null,"abstract":"<p>The corrected QT (QTc) interval is a critical marker for assessing proarrhythmic potential in drug development, while the corrected JT (JTc) interval provides specific insight into ventricular repolarization. This study quantitatively analyzed the relationships of QTc and JTc intervals with age and sex utilizing a large real-world dataset of hospital-based controls and moxifloxacin-treated patients. This retrospective study analyzed 1,039,550 electrocardiograms and associated clinical data extracted from a previously constructed electrocardiogram database, categorizing cases as hospital-based controls (<i>n</i> = 119,882) or moxifloxacin-treated (<i>n</i> = 1586) based on predefined criteria. We observed a general trend of QTc and JTc interval prolongation with age in both groups, with moxifloxacin-treated cases showing longer QTc and JTc intervals than hospital-based controls. Multiple linear regression analysis indicated that in hospital-based controls, QTc and JTc intervals increased with age, with males exhibiting shorter intervals than females. Meanwhile, in moxifloxacin-treated cases, QTc and JTc intervals showed similar age-dependent increases, although no significant sex differences were observed in the QTc interval. Therefore, this study quantified the effects of age and sex on QTc and JTc intervals in hospital-based controls and highlighted similar age-related trends in moxifloxacin-treated cases, underscoring the relevance of age and sex as key factors in interpreting QTc and JTc intervals across diverse clinical contexts.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144190754","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":"PTPN2 and Leukopenia in Individuals With Normal TPMT and NUDT15 Metabolizer Status Taking Azathioprine","authors":"Laura L. Daniel,&nbsp;Puran Nepal,&nbsp;Jacy Zanussi,&nbsp;Alyson L. Dickson,&nbsp;Peter Straub,&nbsp;Tyne W. Miller-Fleming,&nbsp;Wei-Qi Wei,&nbsp;Adriana M. Hung,&nbsp;Nancy J. Cox,&nbsp;Vivian K. Kawai,&nbsp;Jonathan D. Mosley,&nbsp;Charles Michael Stein,&nbsp;QiPing Feng,&nbsp;Ge Liu,&nbsp;Ran Tao,&nbsp;Cecilia P. Chung","doi":"10.1111/cts.70220","DOIUrl":"https://doi.org/10.1111/cts.70220","url":null,"abstract":"<p>Leukopenia is a common dose-dependent side effect of azathioprine, often leading to drug discontinuation. Variants in <i>TPMT</i> and <i>NUDT15</i> are associated with azathioprine-induced leukopenia but only explain 25% of cases. Thus, we aimed to identify novel genetic risk factors among TPMT and NUDT15 normal metabolizers through a genome-wide association study (GWAS). Using BioVU, Vanderbilt's electronic health record linked to genetic data, we assembled a discovery cohort of new users of azathioprine. The analysis was conducted in 1184 new users of azathioprine who had no history of prior thiopurine use or an organ transplant. A replication cohort of 521 patients was derived from <i>All of Us</i>, an NIH-funded project that links healthcare data and genetics. The GWAS was adjusted for sex, age, indication (inflammatory bowel disease, systemic lupus erythematosus, other autoimmune condition, or unknown), concurrent use of xanthine oxidase inhibitors (allopurinol or febuxostat) or immunosuppressants, prior <i>TPMT</i> or <i>NUDT15</i> testing, and 10 principal components of ancestry. In BioVU, 65% of patients were female with a median age of 44 [IQR: 30, 57] and 125 patients developed leukopenia. In <i>All of Us,</i> 69% were female with a median age of 51 [36, 61], and 44 patients developed leukopenia. An intronic variant in <i>PTPN2</i>, rs11664064, reached genome-wide significance in BioVU (OR = 3.61; <i>p</i> = 1.96E-8) and replicated in <i>All of Us</i> (OR = 2.42, <i>p</i> = 0.039). Our finding suggests an association between rs11664064 in <i>PTPN2</i> and azathioprine-induced leukopenia. <i>PTPN2</i> plays a role in immune cell development and differentiation, providing a plausible mechanism for this association.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171829","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":"GLP-1 Agonists for Pediatric Psychopharmacology: Opportunities and Cautions","authors":"Michael Bartkoski,&nbsp;Ethan A. Poweleit,&nbsp;Stephani L. Stancil","doi":"10.1111/cts.70262","DOIUrl":"https://doi.org/10.1111/cts.70262","url":null,"abstract":"<p>Glucagon-like peptide-1 agonists (GLP-1A) are increasingly prescribed to treat obesity and type 2 diabetes mellitus in children and adolescents. Emerging evidence suggesting neuropsychiatric effects presents an opportunity for pediatric psychopharmacology but requires careful consideration of potential adverse effects and risk of misuse. This perspective examines potential applications and cautions surrounding GLP-1As for pediatric mental health, particularly substance use, depression, and eating disorders, and advocates for research and clinical monitoring to ensure their safety and efficacy.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70262","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148596","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":"Added Therapeutic Benefits of Top-Selling Drugs in Japan: A Cross-Sectional Study Using Health Technology Assessment","authors":"Hayase Hakariya,&nbsp;Akihiko Ozaki,&nbsp;Takanao Hashimoto,&nbsp;Frank Moriarty,&nbsp;Hideki Maeda,&nbsp;Tetsuya Tanimoto","doi":"10.1111/cts.70243","DOIUrl":"https://doi.org/10.1111/cts.70243","url":null,"abstract":"<p>It is unclear whether Japanese top-selling drugs have meaningful added therapeutic benefits to justify their high sales. This question is relevant as Japan's healthcare costs are rising consistently, particularly due to increasing drug prices. This cross-sectional study evaluated the added therapeutic benefits of Japan's top-selling drugs in 2021 using ratings from established health technology assessment (HTA) agencies in Canada, France, and Germany. Drug characteristics and benefit ratings were obtained from public databases and HTA agencies, following the established method. Overall, added therapeutic benefit ratings were categorized as binary (high or low). Of 51 identified top-selling drugs in Japan, 43 (86%) had at least one rating from three agencies. Notably, 20 (47%) received low added therapeutic benefit ratings even in our optimistic scenario. Low ratings were more common among small-molecule drugs 15/20 (75%), while high ratings were predominant among biologics 14/23 (61%). Oncology drugs represented the largest category in both high 9/23 (39%) and low 5/20 (25%) groups. Interestingly, 9 drugs (9/16; 56%) approved between 2011 and 2021 received low ratings, compared to 41% (11/27) of those approved before 2011. Additionally, 70% of high-benefit drugs received at least one expedited review, whereas this was 35% for low-benefit drugs. Our findings revealed that many top-selling drugs in Japan had low added therapeutic benefits. Utilizing HTA evaluation frameworks provides valuable insights, particularly in prioritizing drugs based on added therapeutic benefits. While full implementation of such a system in Japan requires further consideration, strengthening HTA processes could help ensure sustainable healthcare costs.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70243","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140539","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":"A Simple Mixed-Effects Modeling for the Precision of Automated Differential Cell Counters Using R","authors":"Karl S. M. Bisselou,&nbsp;Brett G. Hilbers,&nbsp;John N. Mensah","doi":"10.1111/cts.70254","DOIUrl":"https://doi.org/10.1111/cts.70254","url":null,"abstract":"<p>To register their device, manufacturers of automated differential cell counters (ADCC) are required to demonstrate satisfactory precision that meets regulatory standards such as those in 21 CFR 864.5220 in the United States. Mixed-effects models can be used for the estimation of variance components from a range of factors (operators, days, reagent lots, etc.) to characterize the “within-laboratory” or “across laboratories” analytical error associated with ADCCs for a variety of samples representing a plethora of measurand intervals. However, this task can be daunting and time-consuming due to the increasing complexity of the number of blood-associated parameters reported by those devices and the iterative calculations over numerous factors. In this paper, we propose a simple-to-follow <i>R</i> algorithm that overcomes these challenges and provides a comprehensive and effective estimation of variance components in a regulatory-ready reporting format.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70254","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118044","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":"Dose Optimization of rhIL-7-hyFc for Patients With Lymphopenia Using a Neonatal Fc Receptor-Mediated Recycling-Based and Target-Mediated Drug Disposition Pharmacokinetic Model","authors":"Hye Seon Jeon,&nbsp;Sang Won Lee,&nbsp;Woojin Jung,&nbsp;Heeyoon Jung,&nbsp;Donghoon Choi,&nbsp;Mi-Sun Byun,&nbsp;Hwi-yeol Yun,&nbsp;Soyoung Lee,&nbsp;Anhye Kim,&nbsp;Jung-woo Chae,&nbsp;Howard Lee","doi":"10.1111/cts.70252","DOIUrl":"https://doi.org/10.1111/cts.70252","url":null,"abstract":"<p>Recombinant human interleukin-7 hybrid Fc (rhIL-7-hyFc) is a homodimer of rhIL-7 fused to a hyFc. Exogenous IL-7 promotes T cell proliferation and increases lymphocyte count, making it a potential treatment option for lymphopenia and cancer. To improve therapeutic efficacy, rhIL-7-hyFc was developed as a long-acting IL-7. This study aimed to create a pharmacokinetic model for rhIL-7-hyFc by incorporating neonatal Fc receptor (FcRn)-mediated recycling and target-mediated drug disposition (TMDD) of the IL-7 receptor. Data were collected from a randomized, double-blind, placebo-controlled phase 1 trial involving 30 healthy volunteers who received single doses of rhIL-7-hyFc. Volunteers received 20 or 60 mg/kg subcutaneously, 60 mg/kg intramuscularly (IM), or a placebo. Clinical data were provided by Genexine Inc. (Seoul, Republic of Korea). A TMDD-FcRn–mediated recycling pharmacokinetic model was developed using NONMEM 7.5 software, assisted by PsN 5.3.1 software. A quasi-steady-state approximation was used to describe drug-receptor and drug-FcRn interactions. The model evaluation included goodness of fit, visual predictive checks, and bootstrap analysis. Based on the pharmacokinetic parameters of the final model, a simulation was conducted to select the dosage regimen, ensuring a probability of at least 0.8 for meeting both safety and efficacy criteria. The model successfully described the pharmacokinetic profiles of 24 patients administered rhIL-7-hyFc. Based on the simulation results, 670–800 μg/kg every 3 weeks, 1010–1530 μg/kg every 6 weeks, and 1510–2190 μg/kg every 9 weeks IM were proposed. These results may help further understand rhIL-7-hyFc characteristics and, moreover, provide guidance for selecting the appropriate dosing regimen in future clinical trials.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70252","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100736","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":"New Horizon in Clinical Development Strategy in Japan Based on New Guideline on Japanese Phase 1 Studies Prior to Multi-Regional Clinical Trials","authors":"Kei Fukuhara,&nbsp;Takako Shimizu,&nbsp;Junichi Yamamoto,&nbsp;Yasuhiro Tsuda,&nbsp;Yosuke Kobayashi,&nbsp;Naomi Nagai,&nbsp;Jun Oikawa","doi":"10.1111/cts.70257","DOIUrl":"https://doi.org/10.1111/cts.70257","url":null,"abstract":"&lt;p&gt;To facilitate more rapid availability of drugs to patients worldwide, it is essential to utilize multi-regional clinical trials (MRCTs) throughout the clinical development, preferably not only in the confirmatory stage but also in the exploratory stage. In Japan, the Ministry of Health, Labour and Welfare (MHLW) has notified several Japan-specific guidelines for MRCTs [&lt;span&gt;1-3&lt;/span&gt;], which contributed to a significant reduction of the time lag to approval of new drugs between Japan and the United States (US)/the European Union [&lt;span&gt;4&lt;/span&gt;]. However, the guidelines required, in principle, to conduct a Japanese Phase 1 study (J-Ph1) to evaluate the safety and pharmacokinetics (PK) of investigational drugs in Japanese before joining MRCTs [&lt;span&gt;1&lt;/span&gt;]. This requirement would be important in terms of safety risk mitigation in Japanese participants to be enrolled in MRCTs. On the other hand, the conduct of an additional J-Ph1 prior to MRCTs could have a negative impact on the strategy for overseas pharmaceutical companies, especially emerging biopharma companies (EBPs), in developing their innovative drugs in Japan, contributing to “drug loss,” which has recently been a major problem in Japan [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To address the drug loss in Japan, the MHLW released a new guideline in December 2023 [&lt;span&gt;6&lt;/span&gt;], which states that, in principle, an additional J-Ph1 before MRCTs is not needed unless it is deemed necessary after assessing whether the safety and tolerability of Japanese participants in the MRCTs can be explained, and the safety is clinically acceptable and manageable based on all the available data. Figure 1 shows a summary of the key consideration points introduced by the guideline. However, its interpretation, especially how to evaluate and judge the differing risks of conducting versus not conducting J-Ph1 before joining MRCTs (Figure 1), was controversial in Japan since the implementation of the guideline has just begun.&lt;/p&gt;&lt;p&gt;In Drug Information Association (DIA) Japan, we launched a community of clinical pharmacology (CP) in 2022, and have organized several sessions at the DIA Japan annual meetings since 2022. In 2024, we organized a session aimed at ensuring alignment about the guideline among regulators (i.e., Pharmaceuticals and Medical Devices Agency, PMDA), academia, and industry. Here, we summarized and discussed the regulatory, academia, and industry perspectives on the interpretation and expectations for the guideline by referring to presentations and discussions provided throughout the session.&lt;/p&gt;&lt;p&gt;Firstly, Mr. Kobayashi explained that conducting additional J-Ph1 is not the sole cause of the drug loss because other factors, such as not streamlining clinical trials and insufficient dissemination of information overseas on the Japanese pharmaceutical affairs system, are complicatedly interacting. Then, he provided an overview of the guideline, particularly focusing on what has changed and what has remai","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70257","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100806","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":"The Relationship of Indomethacin Exposure With Efficacy and Renal Toxicity Outcomes for Preterm Infants in the Neonatal Intensive Care Unit","authors":"Cindy H. T. Yeung,&nbsp;Deanna C. Sekulich,&nbsp;Allison Scott,&nbsp;Whitney M. Nolte,&nbsp;Kim Gibson,&nbsp;Rachel Su,&nbsp;Mhd Wael Alrifai,&nbsp;Susan M. Lopata,&nbsp;Tamorah Lewis,&nbsp;Jeff Reese,&nbsp;Anil Maharaj","doi":"10.1111/cts.70251","DOIUrl":"https://doi.org/10.1111/cts.70251","url":null,"abstract":"<p>Indomethacin is commonly used in the Neonatal Intensive Care Unit (NICU) for intraventricular hemorrhage (IVH) prophylaxis and patent ductus arteriosus (PDA) treatment, yet unpredictable clinical efficacy and toxicity occur with standard weight-based dosing. Model-informed precision dosing (MIPD) produces individualized doses to overcome deficiencies of standard dosing. To identify an indomethacin therapeutic index for MIPD to target, exposure–response relationships (ERRs) were determined. Indomethacin pharmacokinetic and demographic data collected from preterm infants treated at two US NICUs were leveraged. The following ERRs were assessed: (1) AUC_0–∞ and IVH prevention efficacy (non-severe vs. severe), (2) AUC_course (course start to end+12 h) and PDA treatment efficacy (success vs. failure), and (3) <i>C</i>_max and renal toxicity (urine output nadir within 12 h after dose [UOP_nadir]). A previously developed indomethacin population pharmacokinetic model was used to predict exposure estimates. For the ERR analyses, fixed-effect or mixed-effect regression models (linear or logistic) were used. Data from 83 neonates were available for analysis. The regression analyses supported a lack of an ERR for IVH prevention and PDA treatment efficacy, with only gestational age as the significant predictor of IVH severity. <i>C</i>_max was a significant modulator of natural log UOP_nadir and was used to simulate UOP_nadir &lt; 0.5 and &lt; 1 mL/kg/h for renal toxicity. On average, these levels were reached with <i>C</i>_max values of 22 and 14 μg/mL, respectively. Although an ERR exists for indomethacin renal toxicity, the lack of ERR for indomethacin efficacy may indicate that current dosing does not give exposures sufficiently high to observe an ERR.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70251","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100737","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":"Evaluating the Impact of Hepatic or Renal Impairment on Tanimilast (CHF6001) Pharmacokinetics: Two Open-Label, Parallel-Group, Single-Center Studies","authors":"Annalisa Piccinno,&nbsp;Maria Gloria Pittelli,&nbsp;Deborah Balzano,&nbsp;Elisa Rizzo,&nbsp;Pooja Bellatti,&nbsp;Chiara Rostello,&nbsp;Aida Emirova","doi":"10.1111/cts.70261","DOIUrl":"https://doi.org/10.1111/cts.70261","url":null,"abstract":"<p>Tanimilast is an inhaled phosphodiesterase-4 inhibitor in development for chronic obstructive pulmonary disease and asthma. We conducted two studies to evaluate tanimilast pharmacokinetics, one in subjects with mild, moderate, or severe hepatic impairment and matched healthy controls, and one in subjects with mild, moderate, or severe renal impairment and matched healthy controls. Both studies were single-center, open-label, and parallel group; all subjects inhaled a single 800 μg dose of tanimilast. The primary objective was to evaluate systemic exposure of tanimilast in subjects with hepatic or renal impairment, and in matched healthy subjects, in terms of maximum observed plasma concentration (<i>C</i>_max) and area under the plasma concentration–time curve from time 0 to the last quantifiable concentration (AUC_0–t). A total of 44 subjects were enrolled in each study (8 with mild, moderate or severe hepatic/renal impairment, and 20 controls), all of whom completed. In the hepatic impairment study, there were no statistically significant differences in tanimilast <i>C</i>_max and AUC_0–t between controls and subjects with mild or moderate impairment. For severe hepatic impairment, <i>C</i>_max did not differ significantly from controls, but AUC_0–t increased by 104% (point estimate of ratio [90% confidence interval], 204.03 [134.36; 309.81]). In the renal impairment study, there were no statistically significant differences in tanimilast <i>C</i>_max and AUC_0–t between controls and subjects with mild-to-severe impairment. Three subjects had adverse events in each study, all mild-to-moderate, and none were study treatment related. These data suggest that the pharmacokinetics of tanimilast are not impacted by mild-to-moderate hepatic impairment, or by mild-to-severe renal impairment.</p><p><b>Trial Registration:</b> ClinicalTrials.gov (hepatic impairment NCT05373953; renal impairment NCT05431426) and EudraCT (hepatic impairment 2021-003729-31; renal impairment 2021-005567-43)</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70261","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144091728","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}