Cts-Clinical and Translational Science最新文献

{"title":"Association of Vancomycin Plus Piperacillin-Tazobactam With Acute Kidney Injury: Differentiating Pseudo-Injury From True Nephrotoxicity","authors":"Congqin Chen,&nbsp;Rijing Zhou,&nbsp;Jie Fang,&nbsp;Jie Xiao","doi":"10.1111/cts.70258","DOIUrl":"https://doi.org/10.1111/cts.70258","url":null,"abstract":"<p>The combination of vancomycin and piperacillin-tazobactam (VPT) is widely used for severe infections, but its potential synergistic nephrotoxicity remains debated. This study used the FDA Adverse Event Reporting System (FAERS) database via AERSMine to assess the risk of AKI with VPT and vancomycin plus carbapenems (VC), compared to other vancomycin-based regimens to evaluate the hypothesis of <i>pseudo</i>-nephrotoxicity versus true nephrotoxicity. Disproportionality analysis was performed using the reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN). Model 1 included all vancomycin-associated reports, while Model 2 focused on reports from healthcare professionals. In Model 1, a safety signal was detected for overall AKI (ROR: 1.31, 95% CI: 1.26–1.37; IC025: 0.21) and changes in creatinine (ROR: 1.23, 95% CI: 1.10–1.38; IC025: 0.12) with VPT. In contrast, no significant disproportionality signal was observed for changes in other biomarkers (ROR: 0.89, 95% CI: 0.70–1.14; IC025: −0.38), severe AKI (ROR: 0.82, 95% CI: 0.76–0.89; IC025: −0.31), or renal replacement therapy (RRT) initiation (ROR: 1.08, 95% CI: 0.90–1.29; IC025: −0.09). No safety signal of increased risk of AKI was detected for VC versus other vancomycin-containing regimens across all subgroups. Model 2 confirmed this trend. These findings suggest that creatinine-defined AKI with VPT may represent pseudotoxicity rather than true nephrotoxicity. Further research is needed to clarify the safety profile of VPT.</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.70258","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144091727","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":"Restraint-Based ECG and Arterial Pressure Assessment Do Not Reliably Detect Drug Induced QTc Prolongation and Hypotension: Evidence From Case Studies","authors":"Kim A. Henderson,&nbsp;Nicholas Ether,&nbsp;Hugo M. Vargas","doi":"10.1111/cts.70249","DOIUrl":"https://doi.org/10.1111/cts.70249","url":null,"abstract":"<p>Telemetry-based methods are recommended as best practice for monitoring changes in cardiovascular (CV) function in conscious nonrodent species during the development of new chemical entities. Such methods allow for unrestrained data collection in animals over extended time periods with high sensitivity to detect small effects. The CV profile of new drugs is also assessed in repeat-dose toxicology studies, routinely utilizing non-invasive blood pressure, heart rate, and ECG measurement methods that require physical or chemical restraint. These methods are limited to a short “snapshot” data collection period and incur physiological stress and behavioral excitement from handling/restraint during data collection. The resultant sympathetic activation impacts heart rate, blood pressure, and ECG intervals, causing increased variability and reduced sensitivity. Nonclinical best practices have been defined for standalone CV telemetry studies to support an integrated QTc risk assessment (ICH E14/S7B Q&amp;A 5.1 &amp; 6.1) using non-restraint telemetry methods; however, the pharmacological and statistical sensitivity of restraint-based methods used in repeat-dose toxicology studies is a gap. This paper retrospectively analyzed two case studies (AMG 319 and AMG 337) in which proprietary small molecules were evaluated by both non-restraint-based telemetry and restraint-based methods. AMG 319 and AMG 337 caused QTc interval prolongation and hypotension, respectively, in telemetry studies, which were also observed clinically with these compounds. However, in toxicology studies in which restraint-based ECG and blood pressure methods were used, CV effects were missed, blunted, or directionally wrong. These case studies highlight the need for the utilization of unrestrained telemetry methods over restraint-based methods.</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.70249","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100702","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 Pharmaceutical Care in Nursing Home Residents as a Cornerstone for Drug-Related Problems Identification","authors":"Milada Halačová,&nbsp;Marie Mieresová,&nbsp;Dalibor Černý,&nbsp;Ivana Plechatá,&nbsp;Věra Špatenková,&nbsp;Zdeněk Kalvach","doi":"10.1111/cts.70222","DOIUrl":"https://doi.org/10.1111/cts.70222","url":null,"abstract":"<p>Rational prescribing in geriatrics represents an important ethical as well as socio-economic issue. The aim of this project was to analyze the drug-related problems (DRPs) among the Czech nursing home residents and increase public awareness of further possible employment of clinical pharmacists in social care. The project was designed as a multicenter observational study. A total of 16 nursing homes and 800 participants with an average age of 84.6 ± 7.3 years were included in the study. Of them, a DRP was noted in 93.3% of people. The total amount of DRPs identified was 2215, which means an average of 2.8 ± 1.6 DRPs per patient. The most common DRPs identified were ‘overtreatment’ (19.5%), ‘undertreatment’ (12.8%), inappropriate dose (10.6%), recommendations for laboratory monitoring (10.4%) and adverse effects (10.3%). Of different drug classes, BZDs (OR 16.6, 95% CI 1.0–270.2), PPIs (OR 2.5, 95% CI 1.1–5.6) and NSAIDs (OR 4.4, 95% CI 1.1–18.3) were identified to be most commonly associated with DRPs. The risk of DRP identification clearly increased with the number of drugs used, with seven drugs demonstrated as the best cut-off for predicting DRP identification (AUC 0.842, sensitivity 0.602; specificity 0.796). ‘SENIOR’ project has confirmed a high rate of excessive polypharmacy among nursing home residents in the Czech republic resulting in high risk of potential and manifested DRPs. The project emphasized the role of clinical pharmacists in optimizing safety and effectiveness of treatment among older nursing home residents.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70222","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144091437","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":"Enhancement of Statin Effects on Lipid Lowering and Reduction of Cardiovascular Risk Score by (−)-Epicatechin in Proof-of-Concept Pilot Study","authors":"Cameron K. Ormiston,&nbsp;Aryana Pazargadi,&nbsp;Ashley Rosander,&nbsp;Guillermo Ceballos,&nbsp;Francisco Villarreal,&nbsp;Pam R. Taub","doi":"10.1111/cts.70236","DOIUrl":"https://doi.org/10.1111/cts.70236","url":null,"abstract":"<p>Statins play an instrumental role in reducing and managing atherosclerotic cardiovascular disease (ASCVD) but can be difficult to tolerate due to muscle-associated side effects. There remains an unmet need for strategies that improve statin tolerance and synergize their effect on atherogenic lipids. (−)-Epicatechin (Epi) is a natural flavonoid that can improve lipid biomarkers and mitochondrial function. This study explored the capacity of Epi to augment statin's beneficial effects on lipid profile and ASCVD risk parameters. In total, 19 patients completed a randomized, double-blind placebo-controlled trial. The study consisted of two cohorts. Cohort 1 consisted of healthy patients with elevated low-density lipoprotein (LDL) &gt; 100 mg/dL and was used to determine appropriate Epi dosing. Cohort 2 consisted of patients with metabolic syndrome. Patients were randomized into statin-only (<i>n</i> = 8; 5 in Cohort 2) or statin + Epi (<i>n</i> = 11; 8 in Cohort 2) for 3 months. VO₂ max and lipid biomarkers were assessed at baseline and at the end of 3 months. Final analysis included Cohort 2 only. The statin + Epi group saw significant beneficial changes in total cholesterol (<i>p</i> = 0.002) and non-HDL cholesterol (<i>p</i> = 0.007). There was a significantly larger increase in HDL (<i>p</i> = 0.037) and significantly greater decrease in LDL particle number (<i>p</i> = 0.0003) and small LDL particle number (<i>p</i> = 0.003) among the statin + Epi group compared to statin-only. Ten-year ASCVD risk was significantly lower at end-of-study for the statin + Epi arm compared to statin-only (<i>p</i> &lt; 0.05). No VO₂ max differences were found. This is the first proof-of-concept study to show combination therapy of a statin with Epi is safe and effective in augmenting statin-associated improvements in lipid biomarkers.</p><p><b>Trial Registration:</b> ClinicalTrials.gov: NCT02490527</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70236","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085506","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":"Development and Validation of an Approach to Assessing Clinical Relevance of Potential Drug–Drug Interactions Inducing Rare but Serious Adverse Events","authors":"Menghuan Song,&nbsp;Hui Zhou,&nbsp;Zhirong Yang,&nbsp;Yunfeng Lai,&nbsp;Carolina Oi Lam Ung,&nbsp;Hao Hu","doi":"10.1111/cts.70253","DOIUrl":"https://doi.org/10.1111/cts.70253","url":null,"abstract":"<p>Evaluating clinical relevance of potential drug–drug interactions is significant for managing safety risks. However, current approaches to the evaluation lack data on rare but serious adverse events. This study aims to develop an approach to assessing clinical relevance of potential drug–drug interactions that induce rare and serious adverse events, and test its performance. In the development, three key dimensions for evaluating clinical relevance were synthesized based on a literature review. A systematic five-step approach was proposed through designated dimensions and discussions within the research team. Subsequently, the approach was applied to patients with depression to validate its ability of demonstrating the dimensions, and exacting data on rare but serious adverse events. The test results showed varying signal intensities among different drug combinations in relation to adverse events including serotonin syndrome, long QT syndrome, and Torsade de Pointes. Advanced age was identified as a confounding factor for the QT prolongation signal. These findings operationalize Dimension one: Probabilities and risk factors for the occurrence of rare and serious adverse events. Besides, in the test, fatality occurred in 22.01% of the cases having drug-triggered QT prolongation. Advancing age was associated with the fatality (odds ratio = 1.03, 95% confidence interval = 1.01–1.07). The findings manifested Dimension two: Magnitude of adverse events and associated factors. Dimension three was achieved by findings of median time-to-onset of fatal serotonin syndrome and QT prolongation, which was one and 8 days, respectively. In summary, the proposed approach demonstrates effects in assessing the clinical relevance of potential drug–drug interactions.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144091438","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":"Physiologically Based and Population Pharmacokinetic Modeling of Midazolam in Children With Obesity Using Real-World Data","authors":"Sean McCann,&nbsp;Victória E. Helfer,&nbsp;Stephen J. Balevic,&nbsp;William J. Muller,&nbsp;John N. van den Anker,&nbsp;Amira Al-Uzri,&nbsp;Marisa L. Meyer,&nbsp;Sarah G. Anderson,&nbsp;Sitora Turdalieva,&nbsp;Andrea N. Edginton,&nbsp;Daniel Gonzalez,&nbsp;the Best Pharmaceuticals for Children Act Pediatric Trials Network Steering Committee","doi":"10.1111/cts.70247","DOIUrl":"https://doi.org/10.1111/cts.70247","url":null,"abstract":"<p>Children represent a highly complex and variable population for treatment, including interindividual differences in drug dose–exposure. Midazolam has been used as a sedative for hospitalized children on- and off-label; however, factors affecting interindividual variability (IIV) in observed clearance for this population are not fully understood and can result in extreme under- or overexposure. Obesity has been described as a significant influence on midazolam in adolescents, which could potentially alter drug exposure. The goal of this study was to use two modeling strategies to evaluate dose–exposure of midazolam in children with and without obesity. Population pharmacokinetic modeling assessed whether measures of obesity status would explain some of the observed IIV for midazolam clearance. In all, 164 plasma concentrations were collected from 93 participating children, many with obesity. Covariate modeling did not identify any factors influential to clearance beyond body weight. Model IIV was similar to that observed in previous models of critically ill children (coefficient of variation, 175%) along with considerable residual unexplained variability (50.4%). Then, a previously published virtual population of children with obesity was incorporated into an existing physiologically based pharmacokinetic model of midazolam in the open-source PK-Sim software. Dosing simulations for a subset of 46 participants demonstrated minor overpredictions in children with obesity compared to those without. Both models predicted a minor (&lt; 20%) increase in exposure for children with obesity given the same weight-based dose. This research demonstrates the use of population pharmacokinetics combined with physiologically based pharmacokinetic modeling to compare simulated exposures in children with and without obesity.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70247","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143944841","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":"Safety, Pharmacokinetics, and Pharmacodynamics of a 6-h N,N-Dimethyltryptamine (DMT) Infusion in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled Trial","authors":"Katelijne V. van der Heijden,&nbsp;Rob G. J. A. Zuiker,&nbsp;Marije E. Otto,&nbsp;Christopher S. Bryan,&nbsp;Nancy Stewart,&nbsp;Christopher Stillwell,&nbsp;Marieke L. De Kam,&nbsp;Marloes B. van Leuken,&nbsp;Joop M. A. van Gerven,&nbsp;Gabriel E. Jacobs","doi":"10.1111/cts.70234","DOIUrl":"https://doi.org/10.1111/cts.70234","url":null,"abstract":"<p>The serotonergic psychedelic <i>N</i>,<i>N</i>-dimethyltryptamine (DMT) presumably stimulates neuroplasticity in vitro and in vivo, by which it may exert neuroprotective effects during acute ischemic stroke. Since neuroplasticity has been implicated in the mechanism of action of rehabilitative therapy in stroke recovery, a pharmacological augmentation strategy facilitating neuroplasticity could be beneficial. To optimize this treatment strategy, a detailed understanding of the safety, pharmacokinetics, and pharmacodynamics of prolonged DMT administration is required. This randomized, double-blind, placebo-controlled, single ascending dose study administered three intravenous doses of DMT as a 30-s bolus followed by a 6-h infusion: 1.5 mg + 0.105 mg/min, 7.5 mg + 0.525 mg/min, and 5.0 mg + 0.7875 mg/min. Twelve female and seventeen male psychedelic-experienced and naïve healthy participants, with a mean age of 27.3 (SD 10.2, range 19–57) years, were included. No serious adverse events occurred, and all adverse events were mild in intensity and self-limiting. No significant abnormalities in vital signs or 12-lead electrocardiography, and no suicidality or treatment-emergent psychopathology occurred. Moderate interindividual pharmacokinetic variability was observed. Mild psychedelic effects were accompanied by decreases in sustained attention, postural stability, and occipital alpha electroencephalographic power at the highest dose, which peaked rapidly after bolus administration and remained relatively stable or decreased over time. Together, DMT administered intravenously as a 30-s bolus followed by a 6-h infusion and reaching maximal exposures of approximately 35 ng/mL in healthy volunteers was safe and demonstrated rapidly occurring but mild psychedelic effects, providing the basis for future proof-of-mechanism studies in patient populations.</p><p><b>Trial Registration:</b> ClinicalTrial.gov identifier: NCT05559931</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70234","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143939565","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":"Safety, Tolerability, and Pharmacokinetics of Single and Multiple Topical Applications of Sodium Taurodeoxycholate, a Treatment for Atopic Dermatitis","authors":"Heejae Won,&nbsp;Inseung Jeon,&nbsp;Joo-Youn Cho,&nbsp;Seung-Yong Seong,&nbsp;Kyung-Sang Yu","doi":"10.1111/cts.70242","DOIUrl":"https://doi.org/10.1111/cts.70242","url":null,"abstract":"<p>Sodium taurodeoxycholate (TDCA) gel is a novel candidate for the treatment of atopic dermatitis and is currently under clinical development. TDCA is a taurine-conjugated bile acid derivative that acts as a G protein-coupled bile acid receptor agonist and modulates immune responses. This phase 1 study aimed to investigate the safety, tolerability, and pharmacokinetic profile of sodium TDCA after single and multiple topical administrations of sodium TDCA gel in healthy male subjects. Subjects were randomized to receive a single topical administration of sodium TDCA 5, 10, 30, and 50 mg (0.05%, 0.1%, 0.3%, and 0.5% of 10 g) gel or placebo in the single-ascending dose (SAD) study (<i>N</i> = 32), and sodium TDCA 10, 30, and 50 mg (0.1%, 0.3%, and 0.5% of 10 g) gel or placebo for 28 days (<i>N</i> = 24) in the multiple-ascending dose (MAD) study. Safety profiles were assessed based on adverse events (AEs), global irritation score (GIS), and numerical pain rating scale (NPRS). Serial blood samples were collected for 24 h at baseline and up to 168 h post-dose in the SAD study and for 72 h at baseline and up to 240 h post-dose at steady state in the MAD study. No serious AEs were reported and all AEs were mild in severity for both SAD and MAD studies. The plasma concentrations of TDCA did not increase significantly after topical administrations. Changes in the plasma concentrations of TDCA likely reflected the circadian rhythm rather than the administration of sodium TDCA gel.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70242","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143939100","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":"Frequency and Implications of High-Risk Pharmacogenomic Phenotypes Identified in a Diverse Australian Pediatric Oncology Cohort","authors":"Claire Moore,&nbsp;Andreas Halman,&nbsp;Tayla Stenta,&nbsp;Dhrita Khatri,&nbsp;Elizabeth Williams,&nbsp;Roxanne Dyas,&nbsp;Julian Stolper,&nbsp;David A. Elliott,&nbsp;Rachel Conyers","doi":"10.1111/cts.70246","DOIUrl":"https://doi.org/10.1111/cts.70246","url":null,"abstract":"<p>Pharmacogenomics remains underutilized in pediatric oncology, despite the existence of evidence-based guidelines. Implementation of pharmacogenomics-informed prescribing could improve medication safety and efficacy in pediatric oncology patients, who are at high risk of adverse drug reactions. This study examines the prevalence of high-risk pharmacogenomic phenotypes and the prescription of relevant medications in a diverse Australian pediatric oncology cohort, highlighting the potential impact of pharmacogenomic testing in this unique population. Whole genome sequencing data from 180 patients were analyzed to assess 14 genes with evidence-based pharmacogenomic guidelines relevant to pediatric oncology. Over 90% of patients had at least one high-risk phenotype, with 20% presenting four or more. Ondansetron, mercaptopurine, omeprazole, pantoprazole, and voriconazole were commonly prescribed medications that have pharmacogenomic prescribing recommendations, with the latter three showing the highest actionability rates. High-risk phenotypes were most frequently observed for <i>CYP2C19</i> and <i>CYP2D6</i>, with 30% of patients having a high-risk phenotype for both genes. This study underscores the potential utility of pharmacogenomics in pediatric oncology patients across a range of pharmacogenes and commonly prescribed medications. The findings support advocacy for implementing broad, pre-emptive pharmacogenomic testing in oncology patients to improve treatment safety and efficacy.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932275","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":"Phase 1 Study Evaluating the Pharmacokinetics, Dose Proportionality, Bioavailability, and Tolerability of Subcutaneous Levothyroxine Sodium (XP-8121)","authors":"Richard Fitch,&nbsp;Diane R. Mould,&nbsp;Valentina Conoscenti,&nbsp;Robbie Huang,&nbsp;Dawn Harper","doi":"10.1111/cts.70244","DOIUrl":"https://doi.org/10.1111/cts.70244","url":null,"abstract":"<p>Levothyroxine sodium has been the cornerstone of hypothyroidism management worldwide, with daily oral administration (PO) recognized as standard of care. Oral administration of levothyroxine, however, poses challenges due to variability in pharmacokinetics (PK), influenced by factors such as gastrointestinal absorption, food/drug interactions, and patient adherence. XP-8121 (levothyroxine for subcutaneous administration) is a ready-to-use, subcutaneous (SC) injection formulation of levothyroxine in Phase 3 development. This Phase 1, single-center, 2-part study aimed to characterize the PK and dose proportionality of XP-8121 SC compared to 600 μg oral Ievothyroxine in healthy adults. Additionally, the study evaluated the safety and tolerability of XP-8121 and incorporated population pharmacokinetic (PPK) modeling to support future development. Part 1 was a randomized, open-label, crossover, fixed-sequence study (<i>n</i> = 30). Dose linearity was evaluated by escalating XP-8121 SC doses up to 1200 μg. Part 2 was an open-label, single-period study (<i>n</i> = 30) evaluating PK characteristics of a single dose of XP-8121 SC (1500 μg), potential clinical exposure range, and dose proportionality. After oral levothyroxine administration, baseline-adjusted levothyroxine concentration increased rapidly in plasma (<i>T</i>_max median: 3.1 h); absorption for all XP-8121 SC doses was slower compared to 600 μg oral levothyroxine, and levels remained elevated for 4–5 days before decreasing. Dose proportionality was confirmed, and safety results were similar between all groups. PPK analysis results suggested that weekly doses of XP-8121 SC at four times the daily oral levothyroxine dose provide similar exposure at steady state (AUC_ss). Overall, these data for XP-8121 provide adequate predictive performance to inform future phase 2 studies.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70244","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926158","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}