Cts-Clinical and Translational Science最新文献

{"title":"Pharmacokinetics of Bocidelpar, ASP0367, in Renal and Hepatic Impairment: Results From Two Phase 1 Studies","authors":"Megumi Iwai,&nbsp;Nakyo Heo,&nbsp;Kentaro Hashimoto,&nbsp;Sayuri Guro,&nbsp;Selina Moy,&nbsp;Anna Spence,&nbsp;Tomasz Wojtkowski,&nbsp;Lauren Benner,&nbsp;Melanie Helmick,&nbsp;Tong Zhu,&nbsp;Brian C. Ferslew","doi":"10.1111/cts.70310","DOIUrl":"https://doi.org/10.1111/cts.70310","url":null,"abstract":"<p>Bocidelpar is a peroxisome proliferator-activated receptor δ modulator designed to address mitochondrial impairment. Two open-label, single-dose phase 1 studies (NCT05117294/NCT04942964) investigated the effect of severe renal or mild/moderate hepatic impairment on bocidelpar pharmacokinetics and safety. Adult participants received 75 mg bocidelpar and underwent serial blood and urine sampling over 4 days to evaluate the pharmacokinetics of bocidelpar. Thirteen participants were included in the renal cohort (severe impairment, <i>n</i> = 7; healthy participants, <i>n</i> = 6). A minimal increase was observed in the maximum concentration (C_max) of the severe impairment group versus healthy participants (geometric least squares mean [GeoLSM] ratio [90% CI], 139.66% [86.33, 225.92]). No clear changes were observed in the area under the curve (AUC). Twenty-five participants were included in the hepatic cohort (mild impairment, <i>n</i> = 8; moderate impairment, <i>n</i> = 8; healthy participants, <i>n</i> = 9). Compared with matched controls, increased C_max was observed in the mild (GeoLSM ratio [90% CI], 181.37% [95.47, 344.56]) and moderate (GeoLSM ratio [90% CI], 298.78% [145.00, 615.65]) impairment groups. Mild impairment did not substantially affect the AUC_inf versus matched controls (GeoLSM ratio [90% CI], 110.73% [82.16, 149.24]); however, it was higher in the moderate impairment group versus matched controls (GeoLSM ratio [90% CI], 195.58% [115.26, 331.88]). Across both studies, five treatment-emergent adverse events were observed in five participants; all were considered mild in severity. Overall, bocidelpar was well tolerated and had an acceptable safety profile. Severe renal impairment had a minimal effect on bocidelpar pharmacokinetics, while moderate hepatic impairment resulted in increased bocidelpar concentration and exposure compared with matched controls.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70310","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758470","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":"Ultrasound Renal Denervation Attenuates Early Cardiac Remodeling After Acute Myocardial Infarction in a Swine Model of Hypertensions and Dyslipidemia: A Pilot Study","authors":"Thomas E. Sharp III,&nbsp;Amy L. Scarborough,&nbsp;Amelia G. Haydel,&nbsp;J. Stephen Jenkins,&nbsp;Marloe Prince,&nbsp;Aashish Gupta,&nbsp;Florian Rader,&nbsp;Zhen Li,&nbsp;David J. Lefer,&nbsp;Traci T. Goodchild","doi":"10.1111/cts.70289","DOIUrl":"https://doi.org/10.1111/cts.70289","url":null,"abstract":"<p>Acute myocardial infarction (AMI) patients typically present with a constellation of one or more risk factors including hypertension, dyslipidemia, obesity, or diabetes. Neurohormonal modulation has been a mainstay pharmacotherapy in patients; however, patient compliance is a major obstacle towards clinical efficacy due to side effects and lifelong drug regimens. FDA approval of ultrasound renal denervation (uRDN) for the treatment of resistant hypertension raises the possibility of uRDN therapy for additional disease states involving sympathetic overactivity. In the current pilot study, we sought to explore if prior uRDN has cardioprotective effects against AMI in a comorbid-laden minipig model. Göttingen minipigs (female) were subject to mineralocorticoid excess and a Western high-fat, high-salt diet to induce hypertension, obesity, and hyperlipidemia. Minipigs were randomized to bilateral uRDN (<i>n</i> = 5) treatment or sham-RDN (<i>n</i> = 5) after 4 weeks. After 6 weeks of hypertension and Western high-fat, high-salt diet, animals were subjected to a 75-min left anterior descending coronary artery occlusion followed by 2 weeks of reperfusion. Markers of renal nerve viability, ischemic injury, and cardiac structure and function were assessed. In the uRDN treatment group, there was reduced renal norepinephrine content, improved survival, and reduced myocardial infarct area and calcification compared to sham-RDN treatment. Preservation of the myocardial performance Tei index indicated preserved systolic and diastolic function 2 weeks post AMI. The beneficial effects of uRDN were independent of any reductions in blood pressure. Our pilot study provides new preliminary evidence regarding the efficacy of uRDN in a preclinical large animal model of AMI that features clinically relevant comorbidities.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70289","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740552","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":"Effects of Esketamine Combined With Remimazolam Tosylate on Hemodynamics During Cardiovascular Anesthesia","authors":"Lei Xi,&nbsp;Hui Liu,&nbsp;XiaoJuan Tang,&nbsp;ZhenZhen Jiang","doi":"10.1111/cts.70232","DOIUrl":"https://doi.org/10.1111/cts.70232","url":null,"abstract":"<p>This study aimed to evaluate the effects of esketamine combined with remimazolam tosylate on hemodynamic stability, cerebral oxygen metabolism, and cognitive outcomes in patients undergoing heart valve replacement. Seventy-eight patients were randomized to Group C (dexmedetomidine hydrochloride) or Group R (esketamine + remimazolam tosylate). The following parameters were measured: multiple time points, including mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), arterial-jugular vein oxygen content difference (Da-jvO₂), cerebral oxygen uptake rate (CERO₂), and biomarkers of myocardial injury (cTnI, CK-MB, FABP) at baseline (T0), incision (T1), sternotomy (T2), pre-cardiopulmonary bypass (T3), and post-surgery (T4). Cognitive function was assessed using the Mini-Mental State Examination (MMSE) and Confusion Assessment Method (CAM). Group R showed prolonged values of lower RR in T1 to T4 than Group C (<i>p</i> &lt; 0.05). The Da-jvO₂ and CERO₂ were found to be much higher in Group R in T2, T3, and T4 (<i>p</i> &lt; 0.05). This is an indication of improved cerebral oxygen metabolism. MMSE scores were elevated in Group R: the incidence of delirium and CAM Scores were lower compared with Group C (<i>p</i> &lt; 0.05). This indicates better cognitive outcomes. Also, cTnI, CK-MB, and FABP, myocardial injury markers, were significantly reduced in Group R at postoperative 24 and 72 h (<i>p</i> &lt; 0.05), indicating reduced myocardial injury. The combination of esketamine and remimazolam tosylate offers hemodynamic stability, enhances cerebral oxygen metabolism, improves cognitive function, and reduces myocardial injury in patients undergoing heart valve replacement surgery. This approach might provide significant benefits in cardiovascular anesthesia.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70232","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144716611","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":"Comparative Risk of Major Bleeding With Concomitant Use of Oral Anticoagulants and Corticosteroid Bursts","authors":"Tsung-Chieh Yao,&nbsp;Sheng-Mao Chang,&nbsp;Yi-Fen Tsai,&nbsp;Shuo-Ju Chiang,&nbsp;Hui-Ju Tsai","doi":"10.1111/cts.70311","DOIUrl":"https://doi.org/10.1111/cts.70311","url":null,"abstract":"<p>The choice of oral anticoagulants and oral corticosteroid (OCS) burst cotherapy may influence the risk of major bleeding; however, this risk remains poorly characterized. We aimed to quantify the comparative safety of non–vitamin K oral anticoagulants (NOACs) versus warfarin on major bleeding while receiving OCS burst cotherapy among patients with atrial fibrillation. A nationwide population-based cohort study was conducted using the National Health Insurance Research Database. We examined associations between NOACs (edoxaban, apixaban, dabigartran, or rivaroxaban) or warfarin with OCS burst cotherapy and major bleeding. We measured the risk by estimating incidence, incidence risk ratios (IRRs), and adjusted hazard ratios (AHRs) after adjusting for baseline differences using overlap weighting. In this study, among 239,693 patients receiving oral anticoagulants, 50,390 (21%) received at least one OCS burst, defined as OCS use for less than 30 days, were included. A lower risk of major bleeding related to OCS burst cotherapy with NOACs versus warfarin was noted (AHR = 0.57 [95% CI = 0.52–0.61]). The greatest incidence was observed in patients with warfarin and OCS burst cotherapy (67.30 per 1000 person-years). The incidence for patients prescribing OCS burst cotherapy with edoxaban (30.36 per 1000 person-years; IRR = 0.45 [95% CI = 0.38–0.53]), apixaban (34.93 per 1000 person-years; IRR = 0.52 [95% CI = 0.45–0.60]), dabigatran (42.47 per 1000 person-years; IRR = 0.63 [95% CI = 0.56–0.72]), and rivaroxaban (46.99 per 1000 person-years; IRR = 0.70 [95% CI = 0.63–0.77]), separately, was lower than that with warfarin. The results reveal that the incidence of major bleeding was lowest for edoxaban and highest for warfarin, with notable differences in incidence rates across NOACs among patients receiving oral anticoagulants and OCS burst cotherapy.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705379","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":"Proof of Pharmacology, Safety, and Pharmacokinetics of the Novel TRPA1 Antagonist BI 1839100: A Randomized, Placebo-Controlled, Parallel Group, First-In-Human Study in Healthy Male Participants","authors":"Marella C. E. van Ruissen,&nbsp;Sebastiaan J. W. van Kraaij,&nbsp;Jana Wolfova,&nbsp;Franziska E. Herrmann,&nbsp;Yanick Botilde,&nbsp;Lutz Wollin,&nbsp;Naomi B. Klarenbeek","doi":"10.1111/cts.70290","DOIUrl":"https://doi.org/10.1111/cts.70290","url":null,"abstract":"<p>BI 1839100 is a selective antagonist of transient receptor potential ankyrin 1 (TRPA1). Topically applied TRPA1-agonistic allyl isothiocyanate (AITC), inducing non-invasively measurable increased dermal blood flow (DBF), is known as a skin challenge model to assess TRPA1-target engagement and pharmacodynamic (PD) activity of TRPA1 inhibitors. This study aims to support the pharmacological rationale of BI 1839100 based on preclinical evidence and to test its safety, pharmacokinetic (PK) profile, and PD effects using an AITC skin challenge in a phase I first-in-human clinical study. In vitro and in vivo experiments were conducted in human TRPA1-overexpressing human embryonal kidney (HEK)293 cells and mice, respectively. Exposure to BI 1839100 and AITC demonstrated a BI 1839100 exposure-related reduction of AITC-induced Ca²⁺ increase in HEK293 cells and skin edema in mice. Healthy male participants, aged 18–45 years, were randomized within 10 cohorts in the single-ascending dose part (<i>n</i> = 80) and two cohorts in the PD part (<i>n</i> = 32). All received single doses of BI 1839100/placebo followed by safety and PK measurements. In the PD part, participants underwent an AITC skin challenge twice; at baseline and at time to peak drug concentration after BI 1839100/placebo administration. No significant imbalance in occurrence of adverse events was detected between single doses of BI 1839100 up to 300 mg and placebo, and PK profiles were dose-proportional in the 40–300 mg range. BI 1839100 demonstrated a dose-dependent inhibitory effect on DBF after the AITC skin challenge, indicating TRPA1-targeted pharmacological activity and potentiating BI 1839100 for further clinical development for a broad range of TRPA1 antagonistic applications.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70290","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695927","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 Multicenter Randomized Controlled Study on Pharmacokinetic-Guided Vancomycin Use in Children With Severe Infections","authors":"Fuxiang He,&nbsp;Ya Yang,&nbsp;Bo Zhou,&nbsp;Chengcheng Li,&nbsp;Yu Feng,&nbsp;Xuexin Wang,&nbsp;Haifeng Liu,&nbsp;Yuhang Hu,&nbsp;Hongmin Fu,&nbsp;Yingbo Zou,&nbsp;Guoying Zhang,&nbsp;Jianli Chen,&nbsp;Yueqiang Fu,&nbsp;Shufang Xiao,&nbsp;Lan Hu,&nbsp;Chengjun Liu","doi":"10.1111/cts.70309","DOIUrl":"https://doi.org/10.1111/cts.70309","url":null,"abstract":"<p>This study is a multicenter, randomized controlled prospective trial aimed at evaluating the effects of two vancomycin pharmacokinetics/pharmacodynamics (PK/PD) parameters on clinical outcomes in children with different severe infections: trough concentration (<i>C</i>_min) and the area under the curve (AUC_0-24/MIC). From January 2023 to December 2024, 472 pediatric patients from seven hospitals in Southwest China were included in the present study. These patients were randomly assigned to the AUC_0-24/MIC group or the <i>C</i>_min group. After excluding 75 patients with renal function impairment caused by the primary disease, three patients with incomplete data, and one patient who received vancomycin for less than 48 h, 393 patients were finally enrolled for the present study. Then, the vancomycin treatment for children was evaluated using two PK/PD parameters, to guide clinical efficacy and monitor the incidence of adverse reactions: AUC_0-24/MIC, with a target value of 400–600 mg·h/L; trough concentration (<i>C</i>_min), with a target value of 5–15 mg/L. The results indicated that there were no significant differences between the two groups in terms of daily dose, clinical efficacy, and adverse reactions. However, patients in the <i>C</i>_min group had significantly shorter pediatric intensive care unit (PICU) stays (<i>Z</i> = −2.05, <i>p</i> = 0.04), and patients in the 28-day to 1-year-old subgroup had shorter mechanical ventilation times (<i>Z</i> = −2.25, <i>p</i> = 0.024). Both <i>C</i>_min and AUC_0-24/MIC were effective in guiding the vancomycin treatment for children with severe infections. However, patients in the <i>C</i>_min group presented with advantages in PICU stay and ventilation duration.</p><p><b>Trial Registration:</b> China Clinical Trial Registry: ChiCTR2300067373</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70309","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688226","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":"Linkage Between Hemoglobin to High Density Lipoprotein-Cholesterol Ratio and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Nationally Representative Study","authors":"Zhiping Liu,&nbsp;Huifen Yin,&nbsp;Wenhao Li,&nbsp;Jinhua Zhang","doi":"10.1111/cts.70308","DOIUrl":"https://doi.org/10.1111/cts.70308","url":null,"abstract":"<p>The rising prevalence of metabolic dysfunction—associated steatotic liver disease (MASLD) demands a better understanding of its risk factors. This study aimed to explore the relationship between the hemoglobin to high density lipoprotein-cholesterol ratio (HHR) and MASLD. Data from 3121 participants sourced from the National Health and Nutrition Examination Survey (NHANES) were analyzed. Weighted logistic regression models were constructed to evaluate the associations between HHR and MASLD. Subgroup analyses were conducted to probe potential heterogeneity, and sensitivity analyses, through redefining the CAP cut-off for hepatic steatosis, were employed to affirm the robustness of the observed associations. Increased HHR was independently associated with a higher risk of MASLD. Notably, this association was pronounced among smokers. While a preliminary positive correlation between HHR and liver fibrosis in MASLD patients was noted, it dissipated upon full adjustment. Sensitivity analysis confirmed the stability of the association between HHR and MASLD. Our study reveals a significant positive correlation between HHR and MASLD, with smoking status emerging as a modulatory factor.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70308","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144672739","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 Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Modeling of Serum M-Protein Response for Modakafusp Alfa in a Phase 1/2 Study of Patients With Relapsed or Refractory Multiple Myeloma","authors":"Cheryl Li,&nbsp;Andrew Santulli,&nbsp;Scott Van Wart,&nbsp;Lili Yang,&nbsp;Kaveri Suryanarayan,&nbsp;Sarah F. Cook,&nbsp;Xavier Parot,&nbsp;Donald E. Mager,&nbsp;Neeraj Gupta","doi":"10.1111/cts.70296","DOIUrl":"https://doi.org/10.1111/cts.70296","url":null,"abstract":"<p>Modakafusp alfa (TAK-573) is a novel, first-in-class fusion protein of a humanized anti-CD38 IgG4 kappa antibody fused to attenuated human interferon alfa-2b. It acts as an agonistic innate immunity enhancer through targeted interferon (IFN) signaling and has been investigated as an immune-oncology therapeutic agent in patients with relapsed/refractory multiple myeloma (RRMM). Population PK analysis and sequential PK-PD analysis of serum M-protein (MP) as a primary marker of tumor burden in RRMM were conducted using dose escalation (Part 1) and dose expansion (Part 2) data from 96 RRMM patients enrolled in the Phase 1/2 iinnovate-1 trial. After exploring various structural PK models with different levels of mechanistic complexity, a Michaelis–Menten approximation model that included an anti-drug antibody (ADA) binding model adequately captured the nonlinear PK of modakafusp alfa and the apparent time-varying impact of ADA on the PK. Body weight was a significant predictor of central volume of distribution (exponent of 0.51) but was not predictive of elimination-related parameters given both catabolic and likely target-mediated elimination processes. Serum MP data from patients evaluable at baseline were adequately characterized using the Claret tumor growth inhibition and drug resistance model, with antitumor drug effect using an E_max model. The population PK and PK-PD modeling results supported model-informed drug development for modakafusp alfa, including the switch from weight-based to fixed dosing and the selection of two fixed doses for the randomized dose extension (Part 3) phase of the trial to inform future optimal dose selection, which is consistent with the Project Optimus paradigm.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70296","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673147","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":"Concentration–Response Analysis of the Combination of Pyronaridine and Piperaquine on Corrected QT Interval From a Randomized, Double-Blind, Placebo-Controlled Study in Healthy Adults of African Sub-Saharan Origin","authors":"Mathieu Felices,&nbsp;Isabelle Borghini-Fuhrer,&nbsp;Nada Abla,&nbsp;Stephan Chalon","doi":"10.1111/cts.70305","DOIUrl":"https://doi.org/10.1111/cts.70305","url":null,"abstract":"<p>A novel oral combination of the long-acting antimalarials pyronaridine (PYR) and piperaquine (PQP) has potential for malaria chemoprevention. This single-center randomized, double-blind, placebo-controlled study assessed the effects of PYR and PQP alone and when co-administered on Fridericia-corrected QT interval (QTcF). Between February 14, 2022, and May 31, 2022, thirty-seven healthy black adults of African sub-Saharan origin were enrolled and randomized to PYR + PQP (<i>n</i> = 15), PYR + placebo (<i>n</i> = 8), PQP + placebo (<i>n</i> = 8) or double placebo (<i>n</i> = 6) administered once daily (fasted) for 3 days at doses approved for malaria treatment. Triplicate digitalized electrocardiogram (ECG) recordings and pharmacokinetic samples were taken at matched timepoints. Concentration–response analysis was performed for QTcF changes from baseline (ΔQTcF), and the impact of PYR, PQP, and PYR + PQP administration on placebo-corrected ΔQTcF (ΔΔQTcF) was assessed. The final qualified and validated concentration–QTc model included a linear component for PYR and an <i>E</i>_max component for PQP. The maximum predicted effect on ΔΔQTcF on day 3 was +4.94 msec (90% CI 0.338, 9.54) with PYR + placebo, +19.2 msec (14.6, 23.8) with PQP + placebo, and + 23.1 msec (18.5, 27.6) with PYR + PQP. As expected, PQP increased ΔΔQTcF above the regulatory threshold of concern (+10 msec), whereas PYR did not. The small additional increase in ΔΔQTcF with PYR + PQP coadministration was explained mainly by an increase in PQP <i>C</i>_max (1.4-fold) versus monotherapy. In healthy adults, PYR + PQP coadministration does not appear to increase significantly the effect of PQP on ΔΔQTcF versus PQP administered alone. However, further studies are needed in malaria patients to confirm these findings in the target population.</p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT05160363; EudraCT number: 2021-005698-21</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70305","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673075","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":"Sensitivity of Tepotinib to Inhibitors or Inducers of CYP3A4 and P-Gp: Drug Interaction Studies and Physiologically-Based Pharmacokinetic Analysis","authors":"Rainer Strotmann,&nbsp;Christian Lüpfert,&nbsp;Axel Krebs-Brown,&nbsp;Alice Ke,&nbsp;Matthias Boedding,&nbsp;Jürgen Heuer,&nbsp;Karen Rowland Yeo,&nbsp;Lisa Benincosa,&nbsp;Karthik Venkatakrishnan","doi":"10.1111/cts.70273","DOIUrl":"https://doi.org/10.1111/cts.70273","url":null,"abstract":"<p>Tepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring <i>MET</i> exon 14 skipping alterations. This work aimed to investigate the potential for drug–drug interactions with strong inhibitors and inducers of both cytochrome P450 (CYP) 3A4/5 and P-glycoprotein (P-gp) with tepotinib. Two clinical studies were conducted to investigate the effect of the strong CYP3A4/P-gp inhibitor itraconazole (200 mg once daily) (NCT05203822) and the strong CYP3A4/P-gp inducer carbamazepine (titrated to 300 mg twice daily) (NCT05213481) on the pharmacokinetics of single dose tepotinib 500 mg (450 mg active moiety) in healthy participants. An investigational physiologically-based pharmacokinetic model, developed leveraging mass balance data, was used to evaluate the mechanisms underlying these interactions. Itraconazole increased tepotinib area under the curve extrapolated to infinity (AUC_0-∞) by 22% (geometric mean ratio [GMR] 122.35%; 90% confidence intervals [CIs] 111.48%, 134.29%), but had no effect on tepotinib <i>C</i>_max (GMR 101.53%, 90% CI: 94.00%, 109.67%). Carbamazepine decreased tepotinib AUC_0-∞ by 35% (GMR 65.15%, 90% CI: 59.80%, 70.88%) and <i>C</i>_max by 11% (GMR 89.31%, 90% CI: 83.43%, 95.60%). None of these changes were considered to be clinically relevant. Single doses of tepotinib were considered safe and well tolerated in both studies. The observed pharmacokinetic interactions were consistent with a low (~17%) contribution of CYP3A4 to tepotinib metabolism without a relevant role for P-gp mediated biliary secretion. The potential of tepotinib to be a victim of modulators of both CYP3A4 and P-gp at the intended posology is considered low.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 7","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70273","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657659","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}