Cts-Clinical and Translational Science最新文献

{"title":"Quantifying Risk of Delayed QT Prolongation of Ipatasertib in Preclinical and Clinical Studies in Cancer Patients","authors":"Victor Poon,&nbsp;Dhruvitkumar Sutaria,&nbsp;Rodney Prell,&nbsp;Wendy Halpern,&nbsp;Lisa Wong,&nbsp;Adam Harris,&nbsp;Justin Wilkins,&nbsp;Kenta Yoshida,&nbsp;Rucha Sane","doi":"10.1111/cts.70298","DOIUrl":"10.1111/cts.70298","url":null,"abstract":"<p>QTc prolongation has been associated with torsades de pointes (TdP) and also with other cardiac diseases. We investigated the effect of ipatasertib, a selective serine/threonine kinase (AKT, protein kinase B) inhibitor, on preclinical models of QTc prolongation as well as across two clinical studies. Preclinical in vitro studies suggested that ipatasertib and its metabolite, M1, were unlikely to inhibit human Ether-à-go-go-Related Gene (hERG) channels at the clinically relevant dose. However, clinical evaluation of ipatasertib and its metabolite in the first-in-human study PAM4743g suggested a mild prolongation of the QTc interval, but the effect was delayed, where the maximum change from baseline QTc seemed to occur 2–4 h after time to maximum drug exposure (T_max). QTc prolongation was further evaluated in a second Phase 1b study, GP42658, with pretreatment QTc measurement for baseline correction and intensive post-baseline QTcF measurements at steady state. The results showed a delayed effect, where peak ΔQTcF occurred 2–4 h after T_max with a mean of 10.9 ms and an upper 95% CI of 19.1 ms. Although a delayed effect was observed, the overall magnitude of the QTc effect was not large, and taken together, ipatasertib may not pose a substantial proarrhythmic risk (i.e., mean increase of &gt; 20 ms) at the intended therapeutic dose of 400 mg.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70298","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646858","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":"Influence of Genetic Variation of GST, CYP, and ABC on the Safety and Efficacy of Cyclophosphamide-Based Therapy","authors":"Zhong-Wei Yao,&nbsp;Qi-Long Li,&nbsp;Wei-Feng Hu,&nbsp;Ling-Hui Pan,&nbsp;Jun-Wen Wu,&nbsp;Wen-Lu Ren,&nbsp;Hui-Tian Jia,&nbsp;Pan-Pan Wang,&nbsp;Zhi-Ying Fu,&nbsp;He Zhu","doi":"10.1111/cts.70301","DOIUrl":"10.1111/cts.70301","url":null,"abstract":"<p>Cyclophosphamide (CTX) is one of the most widely used drugs in the clinical treatment of tumors and autoimmune diseases. The correlation between CYP, GST, and ABC gene polymorphisms and CTX activity and its induced toxicity has been extensively studied, but with inconsistent conclusions. In this study, a meta-analysis protocol was employed to comprehensively evaluate the relationship between the gene polymorphisms, including CYP2C9, CYP2C19, CYP2B6, CYP3A5, GSTA1, GSTM1, GSTT1, GSTP1, ABCB1, ABCC4, and ABCG2, and the safety and efficacy of CTX. Forty-five eligible literatures were retrieved from PubMed, Web of Science, Embase, and China National Knowledge Infrastructure (CNKI) databases. The results showed that CYP, GST, and ABC gene polymorphisms analyzed in the study were not associated with the efficacy but related to the safety of CTX. CYP2C19*2 polymorphism showed low risk with CTX-induced gastrointestinal toxicity (RR, 3.70; 95% CI, 1.60–8.55; <i>p</i> = 0.002). The GSTT1-present genotype showed low risk with hematological (RR, 0.63; 95% CI, 0.42–0.96; <i>p</i> = 0.03), gastrointestinal toxicity (RR, 0.62; 95% CI, 0.41–0.94; <i>p</i> = 0.02) and other toxicities (RR, 0.60; 95% CI, 0.38–0.97; <i>p</i> = 0.04). The GSTP1 (rs1695) wild-type showed low risk with gastrointestinal toxicity (RR, 0.69; 95% CI, 0.52–0.92; <i>p</i> = 0.01). Additionally, the ABCC4 (rs9561778) wild-type also showed low risk with gastrointestinal toxicity (RR, 0.50; 95% CI, 0.28–0.88; <i>p</i> = 0.02). Our findings confirm that the polymorphisms of CYP2C19*2, GSTT1, GSTP1 (rs1695), and ABCC4 (rs9561778) play an important role in predicting the risk of hematological, gastrointestinal, and other toxicities in patients undergoing CTX treatment.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635436","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 and Safety of Polaprezinc Granules Oral Administration in Healthy Chinese Volunteers Under Fasting and Fed Conditions","authors":"Min Xiao,&nbsp;Tian Dou,&nbsp;Jia Ji,&nbsp;Caihua Zhu,&nbsp;Yuan Yuan,&nbsp;Hongmin Zhou,&nbsp;Fangqiong Li,&nbsp;Guang Li,&nbsp;Shuang Li","doi":"10.1111/cts.70278","DOIUrl":"10.1111/cts.70278","url":null,"abstract":"<p>The study aimed to demonstrate bioequivalence between generic and original polaprezinc granules by comparing pharmacokinetic (PK) profiles in healthy Chinese subjects under fasting and fed conditions. This PK investigation was conducted with two independent, randomized, open-label, single-dose, two-period, cross-over studies. Healthy Chinese fasting (<i>N</i> = 24, 75 mg) or fed (<i>N</i> = 24, 300 mg) subjects randomly received a single oral dose of the test or reference polaprezinc granules at each period. Blood samples were collected pre- and post-dose for up to 12 h. Blood zinc was determined using a validated ICP-MS method. Primary PK endpoints were calculated using non-compartmental methods, including peak concentration (<i>C</i>_max) and the areas under the plasma concentration-time curve (AUC_0–t, AUC_0–∞). The geometric mean ratios (GMR) in primary PK endpoints between the test and reference products with 90% confidence intervals (CI) were calculated. Treatment-emergent adverse events were assessed. In the fasting study, <i>C</i>_max, AUC_0–t and AUC_0–∞ were 1.30 ± 0.30 μg/mL, 4.06 ± 1.13 h·μg/mL, and 4.43 ± 1.04 h·μg/mL following 75 mg test product. In the fed study, <i>C</i>_max, AUC_0–t and AUC_0–∞ were 0.91 ± 0.26 μg/mL, 3.26 ± 1.06 h·μg/mL, and 3.37 ± 1.07 h·μg/mL following 300 mg test product. The reference product had comparable PK profiles. All 90% CIs of GMRs in <i>C</i>_max, AUC_0–t and AUC_0–∞ between the two products were within 80.0%–125.0%. Both study products were well-tolerated with no serious adverse events. The generic and original polaprezinc granules were bioequivalent by pharmacokinetic comparisons in healthy Chinese subjects under fasting and fed conditions. The two polaprezinc formulations were well-tolerated with no new safety signals.</p><p><b>Trial Registration:</b> CTR20210011</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70278","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144624737","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":"Consideration on Food Effect Studies for Anticancer Drugs Approved in Japan Between 2001 and 2022","authors":"Maho Shibuya,&nbsp;Hayataka Kubota,&nbsp;Hideki Maeda","doi":"10.1111/cts.70304","DOIUrl":"10.1111/cts.70304","url":null,"abstract":"<p>In developing a new drug, studies to evaluate the food effect (FE) on the drug's pharmacokinetics (FE studies) are generally conducted in healthy subjects in the early stages of clinical development. Conversely, for anticancer drugs, which have many adverse effects, it is assumed that FE studies cannot be conducted in healthy subjects. However, many unknowns exist about how FE on oral anticancer drugs is examined in clinical development. In this study, we aimed to examine the characteristics of conducting FE studies on anticancer drugs approved in Japan to date. Between 2001 and 2022, 70 new oral anticancer drugs had been approved in Japan. Of the 70 drugs, 67 (95.7%) were subjected to FE studies. Ninety-five FE studies were conducted on these 67 oral anticancer drugs. Sixty-three studies (66.3%) were conducted on (1) healthy subjects. Most studies were (2) single-dose, (3) single-dosage arm, (4) nonrandomized, (5) crossover, and (6) with a sample size of 11–30 cases. In addition, 80 (84.2%) of the FE studies were conducted ex-Japan, not in Japan. Furthermore, the results of the chi-square test indicated that “(1) drugs using ex-Japan clinical data” “(2) drugs other than cytotoxic anticancer drugs” “(3) drugs developed ex-Japan” and “(4) drugs with &gt; 100 cases in pivotal trials” were more likely to be subjected to FE studies. In conclusion, in FE studies, clinical trials in healthy subjects rather than patients have already been conducted in response to changes in the modality from cytotoxic drugs to molecular targeted drugs and immune checkpoint inhibitors.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70304","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144624736","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":"Sacituzumab Govitecan Population Pharmacokinetics: Updated Analyses Using HR+/HER2− Metastatic Breast Cancer Data From the Phase 3 TROPiCS-02 Trial","authors":"Abhishek G. Sathe,&nbsp;Aksana K. Jones,&nbsp;Paul M. Diderichsen,&nbsp;Xiaohui Wang,&nbsp;Peter Chang,&nbsp;Wendy Verret,&nbsp;Sandhya Girish","doi":"10.1111/cts.70291","DOIUrl":"10.1111/cts.70291","url":null,"abstract":"<p>Sacituzumab govitecan (SG) is an antibody–drug conjugate composed of a Trop-2–directed antibody coupled to SN-38. SG is approved in multiple countries for pretreated metastatic triple-negative breast cancer (mTNBC) and hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) mBC. Three previously developed population pharmacokinetic (PopPK) models for SG, free SN-38, and total antibody (tAB) in patients with mTNBC or other solid tumors were externally validated using data from 260 patients with HR+/HER2− mBC from TROPiCS-02 (NCT03901339). Pharmacokinetic parameters were re-estimated using data from 789 patients with HR+/HER2− mBC, mTNBC, or other solid tumors from three studies—TROPiCS-02, ASCENT (NCT02574455), and IMMU-132-01 (NCT01631552). Previously developed PopPK models adequately described the data from TROPiCS-02. Typical parameter estimates based on combined dataset for clearance and steady-state volume of distribution were 0.128 L/h and 3.58 L for SG and 0.0155 L/h and 4.29 L for tAB, respectively. The pharmacokinetics of the three analytes (SG, free SN-38, and tAB) in participants with HR+/HER2− mBC were consistent with those observed in mTNBC and other tumor types. The analyses confirmed mild-to-moderate renal impairment, mild hepatic impairment, age, tumor type (based on limited data in non-breast cancer tumor types), baseline albumin level, <i>UGT1A1</i> genotype, or Trop-2 expression did not have a clinically relevant impact on the exposure of the three analytes across populations. These findings support that the SG dosing regimen of 10 mg/kg on Days 1 and 8 of 21-day cycles is adequate for patients with HR+/HER2− mBC.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70291","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615530","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":"Translational Model-Informed Dose Selection for Iruplinalkib, a Selective Oral ALK/ROS1 Tyrosine Kinase Inhibitor","authors":"Guihong Yang,&nbsp;Yimei Wang,&nbsp;Huimin Zhao,&nbsp;Qingmei Zheng,&nbsp;Xinmei Wang,&nbsp;Linchao Jia,&nbsp;Qianqian Xin,&nbsp;Cuicui Ma,&nbsp;Yongpeng Zhang,&nbsp;Shansong Zheng,&nbsp;Xiaoyan Kang","doi":"10.1111/cts.70287","DOIUrl":"10.1111/cts.70287","url":null,"abstract":"<p>We utilized an integrated approach for model-informed dose selection to predict the recommended phase 2 dose (RP2D) of iruplinalkib, a selective oral ALK and ROS1 tyrosine kinase inhibitor. The efficacy and pharmacokinetics data obtained from ROS1 or ALK-overexpressing cell-derived xenograft models were used for pharmacokinetics pharmacodynamics (PKPD) modeling and calculating human iruplinalkib tumor static concentration (TSC). The plasma concentration-time profile based on pooled clinical data was included in population PK (PopPK) analysis. The steady-state plasma concentration-time profile of iruplinalkib was predicted based on 1000 simulated replicates of the analysis dataset overlaid with data from 54 patients who received iruplinalkib at 120, 180, or 240 mg QD. A two-compartment PopPK model with first-order absorption and linear elimination successfully delineated iruplinalkib PK characteristics in mice, with good precision (relative standard error [RSE] &lt; 30%). TSC in humans, estimated using a modified Simeoni model, was 98 and 78 ng/mL for ROS1-positive and ALK-positive tumors, respectively. A two-compartment PopPK model with first-order absorption and first-order elimination was established based on data collected from previous clinical studies, and the model described iruplinalkib PK properties well (RSE &lt; 30%). Iruplinalkib 180 mg QD was predicted to benefit over 90% of the population and recommended as the RP2D. This dose regimen was further validated by results of advanced clinical trials and ultimately incorporated into the prescribing information as the recommended dosage. A translational model-based approach using integrated preclinical PK/PD and PopPK modeling in patients with non-small cell lung cancer is a reliable method to predict RP2D.</p><p><b>Trial Registration:</b> ChiCTR.org.cn number: ChiCTR20170871; ClinicalTrials.gov identifier: NCT03389815; ChinaDrugTrials.org.cn number: CTR20190737</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70287","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606714","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":"Clinical Significance of Drug–Drug Interaction Studies During Therapeutic Peptide Drug Development: Follow-Up Investigation of Therapeutic Peptides Approved Between 2021 and 2024","authors":"Carolina Säll,&nbsp;Upendra Argikar,&nbsp;Constanze Hilgendorf,&nbsp;Hilmar Schiller,&nbsp;Anders Sonesson,&nbsp;Kenichi Umehara,&nbsp;Kai Wang","doi":"10.1111/cts.70288","DOIUrl":"10.1111/cts.70288","url":null,"abstract":"<p>The risk of clinically relevant drug–drug interactions (DDIs) for therapeutic peptides remains unclear, mandating a comprehensive analysis for this modality. In our prior study, we analyzed DDIs for 31 peptide drugs approved between January 2008 and August 2021. Here, we analyze DDI data for an additional nine peptide drugs (trofinetide, nirmatrelvir, danicopan, odevixibat, rezafungin, motixafortide, zilucoplan, vosoritide, and tirzepatide) approved from September 2021 to September 2024, focusing on in vitro and clinical DDI data for metabolism- and transporter-based interactions. All nine peptides investigated CYP inhibition in human liver microsomes (HLMs), with low risk identified for larger peptides (&gt; 2 kDa). Likewise, all nine peptides assessed CYP induction in human hepatocytes, with one peptide showing a risk in vitro (danicopan). Phenotyping investigations varied from standard studies (e.g., HLMs with selective CYP inhibitors) to submission packages without classical phenotyping studies. All nine peptides included information related to in vitro transporter properties, but the level of detail varied between submitted packages. Clinical studies investigating metabolism- or transporter-mediated DDIs were performed for four peptides (all &lt; 2 kDa). Area under the curve changes attributed to the peptide drug were &lt; 2.3 fold. Our expanded dataset now includes 40 therapeutic peptides approved since 2008, providing a unique resource for drug developers. The findings reinforce our previous conclusions regarding the low likelihood of DDIs for larger peptides and a higher risk for smaller peptides with xenobiotic structural properties. This collective data will be invaluable in developing clear and meaningful DDI guidelines for therapeutic peptides.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70288","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582384","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":"Announcing the Biomedical Data Translator: Initial Public Release","authors":"Karamarie Fecho,&nbsp;Gwênlyn Glusman,&nbsp;Sergio E. Baranzini,&nbsp;Chris Bizon,&nbsp;Matthew Brush,&nbsp;William Byrd,&nbsp;Lawrence Chung,&nbsp;Andrew Crouse,&nbsp;Eric Deutsch,&nbsp;Michel Dumontier,&nbsp;Aleksandra Foksinska,&nbsp;Jennifer Hadlock,&nbsp;Kaiwen He,&nbsp;Sui Huang,&nbsp;Robert Hubal,&nbsp;Gregory M. Hyde,&nbsp;Sharat Israni,&nbsp;Kelyne Kenmogne,&nbsp;David Koslicki,&nbsp;Jana Dorfman Marcette,&nbsp;Ewy A. Mathe,&nbsp;Abrar Mesbah,&nbsp;Sierra A. T. Moxon,&nbsp;Christopher J. Mungall,&nbsp;John Osborne,&nbsp;Carrie Pasfield,&nbsp;Guangrong Qin,&nbsp;Stephen A. Ramsey,&nbsp;Justin Reese,&nbsp;Jared C. Roach,&nbsp;Reese Rose,&nbsp;Karthik Soman,&nbsp;Andrew I. Su,&nbsp;Casey Ta,&nbsp;Gaurav Vaidya,&nbsp;Rosina Weber,&nbsp;Qi Wei,&nbsp;Mark Williams,&nbsp;Chunlei Wu,&nbsp;Colleen Xu,&nbsp;Chase Yakaboski,&nbsp;The Biomedical Data Translator Consortium","doi":"10.1111/cts.70284","DOIUrl":"10.1111/cts.70284","url":null,"abstract":"<p>The growing availability of biomedical data offers vast potential to improve human health, but the complexity and lack of integration of these datasets often limit their utility. To address this, the Biomedical Data Translator Consortium has developed an open-source knowledge graph–based system—Translator—designed to integrate, harmonize, and make inferences over diverse biomedical data sources. We announce here Translator's initial public release and provide an overview of its architecture, standards, user interface, and core features. Translator employs a scalable, federated, knowledge graph framework for the integration of clinical, genomic, pharmacological, and other biomedical knowledge sources, enabling query retrieval, inference, and hypothesis generation. Translator's user interface is designed to support the exploration of knowledge relationships and the generation of insights, without requiring deep technical expertise and gradually revealing more detailed evidence, provenance, and confidence information, as needed by a given user. To demonstrate Translator's application and impact, we highlight features of the user interface in the context of three real-world use cases: suggesting potential therapeutics for patients with rare disease; explaining the mechanism of action of a pipeline drug; and screening and validating drug candidates in a model organism. We discuss strengths and limitations of reasoning within a largely federated system and the need for rich concept modeling and deep provenance tracking. Finally, we outline future directions for enhancing Translator's functionality and expanding its data sources. Translator represents a significant step forward in making complex biomedical knowledge more accessible and actionable, aiming to accelerate translational research and improve patient care.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70284","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589935","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":"Population Pharmacokinetics and Exposure–Response Analyses for Capivasertib in Combination With Fulvestrant in Patients With Breast Cancer","authors":"Carlos Fernandez Teruel,&nbsp;Marie Cullberg,&nbsp;Ignacio González-García,&nbsp;Gaia Schiavon,&nbsp;Ling Zhang,&nbsp;Diansong Zhou","doi":"10.1111/cts.70286","DOIUrl":"10.1111/cts.70286","url":null,"abstract":"<p>Capivasertib is a potent, selective pan-AKT inhibitor. In the Phase III CAPItello-291 trial in patients with aromatase inhibitor-resistant, hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, the addition of capivasertib (400 mg twice daily, 4 days on, 3 days off) to fulvestrant significantly improved the dual primary endpoints of progression-free survival in the overall and <i>PIK3CA</i>/<i>AKT1</i>/<i>PTEN</i>-altered population compared with placebo plus fulvestrant and had an acceptable safety profile. Based on data from six Phase I–III trials (<i>N</i> = 851), a three-compartment population pharmacokinetic model was used to generate individual Bayes' capivasertib steady-state exposure parameters (AUC, <i>C</i>_max, and <i>C</i>_min). No relationship between exposure and efficacy (progression-free survival or objective response rate) was identified in CAPItello-291 (<i>n</i> = 394). The safety analysis, which pooled data from CAPItello-291 and a Phase I trial (<i>n</i> = 468), identified significant relationships between capivasertib exposure and the likelihood of an adverse event (AE) leading to dose modification, AE grade ≥ 3, and diarrhea AE grade ≥ 2; whereas, no significant relationships were identified between capivasertib exposure and AE leading to dose discontinuation, serious AE, AE grade ≥ 1, rash AE grade ≥ 2, hyperglycemia AE grade ≥ 1, hyperglycemia AE grade ≥ 3, or increased blood glucose &gt; 13.9 mmol/L. These results support the consistent benefit observed with the intermittent capivasertib dosing schedule of 400 mg twice daily, in combination with fulvestrant, in patients with aromatase inhibitor-resistant, HR-positive/HER2-negative advanced breast cancer without dose adjustment based on intrinsic factors, such as race, age, body weight, renal or hepatic function.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70286","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574147","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":"Effect of Rifampicin on the Pharmacokinetics of Valemetostat and Its Primary Metabolite: A Phase 1 Study in Healthy Participants","authors":"Masaya Tachibana,&nbsp;Shunji Matsuki,&nbsp;Akifumi Kurata,&nbsp;Masato Fukae,&nbsp;Sayaka Shinohara,&nbsp;Takako Shimizu","doi":"10.1111/cts.70279","DOIUrl":"10.1111/cts.70279","url":null,"abstract":"<p>Valemetostat tosylate (valemetostat) is a dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, approved in Japan for the treatment of relapsed or refractory peripheral T-cell lymphoma, including adult T-cell leukemia/lymphoma, and globally under investigation for the treatment of non-Hodgkin lymphomas and solid tumors. Valemetostat is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) in vitro. This phase 1, open-label, single-sequence crossover study assessed the effect of repeated oral doses of rifampicin, a strong CYP3A and P-gp inducer, on the pharmacokinetics (PK) of valemetostat in healthy Japanese participants. In this trial, 20 participants received two doses of valemetostat 200 mg, once alone and once after repeated daily doses of rifampicin 600 mg. Coadministration with rifampicin decreased the maximum plasma concentration (<i>C</i>_max) and area under the plasma concentration–time curve extrapolated to infinity (AUC_inf) of total valemetostat. The geometric least-squares mean ratios (GMR, test/reference) for <i>C</i>_max and AUC_inf were 0.417 [90% confidence interval (CI), 0.319–0.545] and 0.286 [90% CI, 0.225–0.364], respectively. <i>C</i>_max of CALZ-1809a (a major valemetostat oxidative metabolite) increased (GMR, 1.287 [90% CI, 1.036–1.600]), while the AUC_inf decreased (GMR, 0.713 [90% CI, 0.573–0.886]). No treatment-related or Grade ≥ 2 adverse events were reported. These results showed that valemetostat exposure was reduced upon coadministration of rifampicin, suggesting that concomitant use of valemetostat with strong CYP3A and P-gp inducers should be avoided.</p><p><b>Trial Registration:</b> Japan Registry: jRCT2080225242</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70279","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144573859","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}