Journal of Clinical Pharmacology最新文献_第2页

Assessment of Telisotuzumab Vedotin Drug-Drug Interaction Potential Using Physiologically-Based Pharmacokinetic Modeling and Simulations. 使用基于生理的药代动力学建模和模拟评估替索单抗韦多汀-药物相互作用潜力。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-25 DOI: 10.1002/jcph.70108

Md Mahbubul Huq Riad, Priya Brunsdon, Rajeev Menon, Patrick Marroum, Apurvasena Parikh

{"title":"Assessment of Telisotuzumab Vedotin Drug-Drug Interaction Potential Using Physiologically-Based Pharmacokinetic Modeling and Simulations.","authors":"Md Mahbubul Huq Riad, Priya Brunsdon, Rajeev Menon, Patrick Marroum, Apurvasena Parikh","doi":"10.1002/jcph.70108","DOIUrl":"https://doi.org/10.1002/jcph.70108","url":null,"abstract":"Telisotuzumab vedotin (Teliso-V; ABBV-399) is an antibody-drug conjugate (ADC) comprised of the c-Met targeting antibody telisotuzumab (ABT-700) conjugated to the potent cytotoxic monomethyl auristatin E (MMAE). Teliso-V has been evaluated for treating solid tumors and is approved for adults with locally-advanced or metastatic non-squamous non-small cell lung cancer with high c-Met protein overexpression (≥50% tumor cells with strong [+3] staining; determined by FDA-approved test), who have received prior systemic therapy. Here, physiologically-based pharmacokinetic (PBPK) modeling was utilized to evaluate Teliso-V drug-drug interaction (DDI) potential. A published PBPK-model for MMAE as the primary metabolite and a newly-developed telisotuzumab model from existing pre-clinical and clinical trial data were used to create a novel Teliso-V PBPK-model. Unconjugated MMAE release was modeled with drug-to-antibody ratio-specific deconjugation rates, with non-specific and catabolic clearance added to capture half-life and overall PK profile. The Teliso-V model was calibrated and validated using observed clinical trial data, requiring dose-normalized exposure %PEs ≤50%. CYP3A-mediated DDI simulations demonstrated that when Teliso-V was modeled as the victim, a 43% increase and 70% decrease in MMAE AUC were predicted with ketoconazole (strong CYP3A4-inhibitor) and rifampin (strong CYP3A4-inducer) coadministration, respectively. DDI magnitude was comparable to that observed between another approved ADC with the same MMAE payload (brentuximab vedotin) and ketoconazole and rifampin. The current PBPK simulations demonstrated a lack of perpetrator effect of Teliso-V on midazolam, a sensitive CYP3A substrate. The current analysis provides important information on Teliso-V DDI potential and further demonstrates the utility of PBPK models, particularly in oncology, where dedicated DDI studies are challenging.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clinical and Biochemical Factors Associated With Infliximab Pharmacokinetics in Adult Patients With Inflammatory Bowel Disease. 炎症性肠病患者英夫利昔单抗药代动力学相关的临床和生化因素

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-25 DOI: 10.1002/jcph.70111

Ilse A Pool, Ilse Volkerink, Mirthe Stavast, Jos G W Kosterink, Gerard Dijkstra, Paola Mian, Arno R Bourgonje

{"title":"Clinical and Biochemical Factors Associated With Infliximab Pharmacokinetics in Adult Patients With Inflammatory Bowel Disease.","authors":"Ilse A Pool, Ilse Volkerink, Mirthe Stavast, Jos G W Kosterink, Gerard Dijkstra, Paola Mian, Arno R Bourgonje","doi":"10.1002/jcph.70111","DOIUrl":"https://doi.org/10.1002/jcph.70111","url":null,"abstract":"Many patients with inflammatory bowel disease (IBD) do not adequately respond to infliximab, potentially due to individual differences in pharmacokinetics (PK). This study aimed to identify clinical and biochemical variables associated with infliximab PK. Adult IBD patients treated with infliximab and with registered infliximab trough levels between March 1, 2021 and November 22, 2023, were included. Univariable and multivariable linear mixed-effects models were used to evaluate associations between clinical and biochemical covariates and infliximab trough levels. A systematic literature review was conducted to contextualize findings. The study included 259 patients (CD: n = 202; UC: n = 47; IBD-unclassified: n = 10) with 560 infliximab trough levels available for analysis. Higher hemoglobin was associated with lower infliximab levels (IBD: β = 0.668, p = 0.036; UC: β = 1.639, p = 0.018), as were albumin (IBD: β = 0.214, p = 0.002; CD: β = 0.345, p < 0.001) and AST (CD: β = 0.040, p = 0.019). Inverse associations were also found for ALT (UC: β = -0.100, p = 0.016), ALP (CD: β = -0.029, p = 0.021; UC: β = -0.018, p = 0.037) and GGT (IBD: β = -0.015, p = 0.028; UC: β = -0.034, p < 0.001). Endoscopic inflammation was positively associated with infliximab levels in CD (β = 3.402, p = 0.035). Systemic steroid use was associated with lower infliximab levels in UC (β = -4.263, p = 0.013). In conclusion, this study identified several clinical and biochemical variables, including albumin, hemoglobin and GGT across all patients, albumin, AST and ALP in CD, and hemoglobin, ALT, ALP and GGT in UC, that were associated with infliximab trough levels. Given the correlative nature of this study, these results should be interpreted cautiously. These findings merit validation and could inform model-informed precision dosing strategies in IBD clinical care.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of Varying Degrees of Hepatic Impairment on the Pharmacokinetics of Ervogastat, a Diacylglycerol Acyltransferase 2 (DGAT2) Inhibitor, and Clesacostat, an Acetyl-CoA Carboxylase (ACC) Inhibitor. 不同程度肝功能损害对二酰基甘油酰基转移酶2 （DGAT2）抑制剂Ervogastat和乙酰辅酶a羧化酶（ACC）抑制剂Clesacostat药代动力学的影响

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-25 DOI: 10.1002/jcph.70106

Manoli Vourvahis, Arthur J Bergman, Adam G Ogden, Jim Hughes, James R Gosset, Amit S Kalgutkar, Neeta B Amin

{"title":"Effect of Varying Degrees of Hepatic Impairment on the Pharmacokinetics of Ervogastat, a Diacylglycerol Acyltransferase 2 (DGAT2) Inhibitor, and Clesacostat, an Acetyl-CoA Carboxylase (ACC) Inhibitor.","authors":"Manoli Vourvahis, Arthur J Bergman, Adam G Ogden, Jim Hughes, James R Gosset, Amit S Kalgutkar, Neeta B Amin","doi":"10.1002/jcph.70106","DOIUrl":"https://doi.org/10.1002/jcph.70106","url":null,"abstract":"Ervogastat, a diacylglycerol-O-acyltransferase-2 inhibitor, and clesacostat, an acetyl-CoA carboxylase inhibitor, are in clinical development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Study 1 and Study 2 were open-label, Phase 1 trials that assessed the pharmacokinetics (PK) of a single dose of ervogastat (100 mg) and clesacostat (25 mg), respectively, in participants (n = 6/cohort) with mild, moderate, or severe hepatic impairment (HI) and compared to those without HI (reference). Plasma samples were analyzed for both total and unbound concentrations in Study 2 as clesacostat is highly protein bound. In Study 1, compared to participants without HI, ervogastat exposure (AUCinf) was 56%, 65%, and 52% higher in participants with mild, moderate, and severe HI, respectively. However, when excluding PK data from a participant with unexplained low exposures in reference group, ervogastat exposures were similar between those with/without HI. In Study 2, total clesacostat exposure was 36%, 24%, and 19% higher for mild, moderate, and severe HI, respectively, as compared to reference group. Unbound clesacostat exposures were 70%, 83%, and 166% higher for mild, moderate, and severe HI cohorts, respectively, with clesacostat plasma protein binding shown to decrease with increasing HI severity. Ervogastat and clesacostat were well tolerated with no clinically significant laboratory abnormalities or changes in vital signs and/or electrocardiograms observed. Observed exposures in HI studies were consistent with simulated exposures in MASH population. Taking into consideration the safety margins at the highest doses evaluated in Phase 2, no dose adjustment of ervogastat or clesacostat is currently warranted for patients with hepatic impairment. NCT: NCT04091061, NCT03309202.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Physiologically Based Pharmacokinetic Modeling of Lemborexant: Exploration of Doses for Populations with Hepatic Impairment. Lemborexant基于生理学的药代动力学建模：肝损害人群剂量的探索。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-23 DOI: 10.1002/jcph.70110

Wanhong Wu, Guanxing Pan, Xiaoxi Cai, Rongfang Lin, Pinfang Huang, Cuihong Lin

{"title":"Physiologically Based Pharmacokinetic Modeling of Lemborexant: Exploration of Doses for Populations with Hepatic Impairment.","authors":"Wanhong Wu, Guanxing Pan, Xiaoxi Cai, Rongfang Lin, Pinfang Huang, Cuihong Lin","doi":"10.1002/jcph.70110","DOIUrl":"https://doi.org/10.1002/jcph.70110","url":null,"abstract":"Lemborexant, a dual orexin receptor antagonist, is suitable for the long-term treatment of insomnia. It is primarily metabolized in the liver. The aim was to develop physiologically based pharmacokinetic (PBPK) models of lemborexant to provide dosing regimens for populations with hepatic impairment. The PBPK models of lemborexant were developed and validated using PK-Sim for healthy populations and populations with mild, moderate hepatic impairment, respectively. Then, the effect of severe hepatic impairment on lemborexant pharmacokinetics was investigated to determine dosing regimens. The developed model successfully described the pharmacokinetics of lemborexant in healthy and hepatic impairment populations. Mean plasma concentrations of lemborexant were higher in populations with hepatic impairment compared to those with normal hepatic function. The area under the plasma concentration-time curve at steady state (AUCss,24h) values in populations with mild, moderate, and severe hepatic impairment were 1.54-, 2.18-, and 2.08-fold higher, respectively, compared to those with normal hepatic function. Based on the changes in exposure, it is recommended that the maximum dose for populations with severe hepatic impairment should be limited to 5 mg once daily, which is similar to moderate hepatic impairment. The PBPK model can be used as a tool for dose adjustments in populations with hepatic impairment.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Population Pharmacokinetics and Dose Simulation of Levetiracetam in Patients with Epilepsy: Influence of Renal Function and Phenytoin Co-Administration. 癫痫患者左乙拉西坦的人群药代动力学和剂量模拟：肾功能和苯妥英联合给药的影响。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-19 DOI: 10.1002/jcph.70101

Noppaket Singkham, Apinya Boonpeng, Pasiri Sithinamsuwan, Juthathip Suphanklang

{"title":"Population Pharmacokinetics and Dose Simulation of Levetiracetam in Patients with Epilepsy: Influence of Renal Function and Phenytoin Co-Administration.","authors":"Noppaket Singkham, Apinya Boonpeng, Pasiri Sithinamsuwan, Juthathip Suphanklang","doi":"10.1002/jcph.70101","DOIUrl":"https://doi.org/10.1002/jcph.70101","url":null,"abstract":"Levetiracetam (LEV) exhibits considerable interindividual pharmacokinetic variability; however, data in Thai populations remain limited. This study aimed to develop a population pharmacokinetic model of LEV, identify covariates affecting clearance, and inform individualized dosing strategies. A total of 374 LEV plasma concentrations from 264 Thai patients with epilepsy were analyzed using nonlinear mixed-effects modeling. The median age was 65.3 years (range 18.09-97.71). LEV pharmacokinetics was characterized by a one-compartment model with first-order elimination and proportional residual variability. The typical apparent clearance and volume of distribution were estimated at 2.61 L/h and 56.3 L, respectively. Clearance was significantly influenced by creatinine clearance (CrCL), estimated using the Cockcroft-Gault equation with adjusted body weight, and by phenytoin co-administration. Phenytoin increased clearance by 43.1%, while reduced CrCL was associated with lower clearance. Monte Carlo simulations demonstrated that both trough concentrations and the probability of achieving therapeutic targets (12-46 mg/L) declined with increasing CrCL, especially in patients receiving phenytoin. Standard 12-h dosing was generally sufficient for patients with impaired renal function who were not receiving phenytoin. In contrast, subtherapeutic exposure was more frequent in those with preserved or augmented renal function, particularly when phenytoin was co-administered. These findings support the use of higher or more frequent dosing in these subgroups. The final model provides a framework for individualized LEV dosing. Prospective studies are needed to validate these findings and guide their implementation in clinical practice.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Physiologically Based Pharmacokinetic Modeling to Predict Maternal Pharmacokinetic Changes of Topiramate During Pregnancy and Recommend Dose Adjustments. 基于生理的药代动力学模型预测妊娠期间托吡酯的母体药代动力学变化并推荐剂量调整。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-09 DOI: 10.1002/jcph.70105

Yuying Chen, Meng Ke, Wanhong Wu, Cuihong Lin

{"title":"Physiologically Based Pharmacokinetic Modeling to Predict Maternal Pharmacokinetic Changes of Topiramate During Pregnancy and Recommend Dose Adjustments.","authors":"Yuying Chen, Meng Ke, Wanhong Wu, Cuihong Lin","doi":"10.1002/jcph.70105","DOIUrl":"https://doi.org/10.1002/jcph.70105","url":null,"abstract":"Topiramate is increasingly used in the treatment of epilepsy during pregnancy. However, its plasma concentration evidently decreases during pregnancy, which may reduce its efficacy. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of topiramate to simulate maternal and fetal pharmacokinetic changes across different trimesters and to propose dose adjustments. We established a topiramate pregnancy PBPK model in PK-Sim and Mobi. The model was validated using clinically observed data and subsequently used to optimize the dosage during pregnancy. Simulation results showed that the mean steady-state trough plasma concentration of topiramate decreased by 9.4%, 32%, and 46% in the first, second, and third trimesters, respectively. Based on these findings, the dosage should remain unchanged during the first trimester of pregnancy. However, increasing the baseline dose of topiramate by at least 1.5- and 1.9-fold during the second and third trimesters, respectively, may help maintain effective plasma concentrations. This study provides reference information for topiramate dosage adjustment during pregnancy and helps improve its safety and efficacy in pregnant women and fetuses.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Population Pharmacokinetics of Valemetostat and Exposure-Response Analyses of Efficacy and Safety in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma. 伐美他汀在复发/难治性外周t细胞淋巴瘤患者中的人群药代动力学及疗效和安全性暴露反应分析。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-06 DOI: 10.1002/jcph.70100

Hiroyuki Inoue, Xiaoning Wang, Ramon Garcia, Brian Reilly, Masaya Tachibana, YoungJun Yoo, Yvonne Lau, Yang Chen

{"title":"Population Pharmacokinetics of Valemetostat and Exposure-Response Analyses of Efficacy and Safety in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma.","authors":"Hiroyuki Inoue, Xiaoning Wang, Ramon Garcia, Brian Reilly, Masaya Tachibana, YoungJun Yoo, Yvonne Lau, Yang Chen","doi":"10.1002/jcph.70100","DOIUrl":"https://doi.org/10.1002/jcph.70100","url":null,"abstract":"Valemetostat is a dual inhibitor of EZH2/1 approved in Japan for the treatment of relapsed/refractory (R/R) adult T-cell lymphoma/leukemia (ATLL) and R/R peripheral T-cell lymphoma (PTCL). It is administered orally once daily (QD) at 200 mg. Here, we present comprehensive population pharmacokinetic (PPK) and exposure-response (ER) analyses of valemetostat. The PPK model included data from six clinical trials in patients with non-Hodgkin lymphoma, including ATLL/PTCL, or healthy participants. ER efficacy analyses were based on data from one phase 2 clinical trial in patients with PTCL; ER safety analyses used data from three trials in patients with ATLL or PTCL. Valemetostat unbound average concentration up to event was used as the exposure metric. ER analyses included overall response rates for efficacy and six safety endpoints (any Grade ≥3 treatment-emergent adverse event [TEAE]; Grade ≥3 thrombocytopenia, anemia, and neutropenia; and dose reduction and interruption due to TEAEs). Valemetostat pharmacokinetics were well described by a three-compartment model, with a sequential linked zero-/first-order absorption, a saturable binding component in the central compartment, and linear elimination of unbound valemetostat from the central compartment. Alpha-1-acid glycoprotein was the only identified covariate significantly affecting total valemetostat exposure but had no impact on unbound exposure. The ER relationship on efficacy was not significant, and positive relationships were identified for multiple safety endpoints. Safety simulations across different doses suggested an acceptable safety profile for 200 mg QD. Overall, these analyses support the favorable benefit-risk profile of valemetostat at 200 mg QD in patients with R/R PTCL.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Phase 1 Randomized Study: Garadacimab Pharmacokinetics, Safety, and Tolerability After Administration via Autoinjector/Pre-Filled Pen Versus Pre-Filled Syringe in Healthy Participants. 一项1期随机研究：健康人通过自动注射器/预填充笔与预填充注射器给药后加达西单抗的药代动力学、安全性和耐受性

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-06 DOI: 10.1002/jcph.70099

Fiona Glassman, John-Philip Lawo, Mihai Alexandru Bica, Anthony Roberts, David Kormann, Ligia Chialda, Soeren Miethke, Iwona Dziadowiec, Stephen Caltabiano, Thomas Puchalski

{"title":"A Phase 1 Randomized Study: Garadacimab Pharmacokinetics, Safety, and Tolerability After Administration via Autoinjector/Pre-Filled Pen Versus Pre-Filled Syringe in Healthy Participants.","authors":"Fiona Glassman, John-Philip Lawo, Mihai Alexandru Bica, Anthony Roberts, David Kormann, Ligia Chialda, Soeren Miethke, Iwona Dziadowiec, Stephen Caltabiano, Thomas Puchalski","doi":"10.1002/jcph.70099","DOIUrl":"https://doi.org/10.1002/jcph.70099","url":null,"abstract":"Garadacimab is a novel, fully human, anti-activated factor XII monoclonal antibody approved for long-term prophylaxis of patients with hereditary angioedema. This open-label, parallel-group, Phase 1, single-center, bridging study in healthy adults (18-55 years of age) characterized the pharmacokinetics and safety of a single 200 mg subcutaneous injection of garadacimab administered via autoinjector/pre-filled pen (AI/PFP) compared with the pre-filled syringe (PFS) used in previous studies. The aim of the study was to bridge the understanding of the PK and safety of garadacimab between PFS and AI/PFP modes of administration. Participants (N = 132) were stratified by body weight, randomized evenly in six groups by device (AI/PFP or PFS) and injection site (abdomen, thigh, or upper arm). The primary endpoint comprised pharmacokinetic parameter comparison between devices. Safety/tolerability were secondary endpoints. The geometric mean ratio (GMR) for Cmax and AUC0-inf comparing administration by PFS and AI/PFP was close to 1 with 90% confidence intervals within a range of 0.8-1.25, meeting bioequivalence criteria; GMR (90%) was 0.92 (0.81, 1.05) for Cmax and 0.96 (0.87, 1.07) for AUC0-inf. No participants in this study had anti-drug antibodies against garadacimab. Treatment-related emergent adverse events were reported in 9/66 (13.6%) participants in the PFS group and 11/66 (16.7%) participants in the AI/PFP group. Garadacimab 200 mg administered as a single subcutaneous dose via AI/PFP had a consistent safety and tolerability profile to that administered via PFS. These findings support administration of garadacimab via AI/PFP, providing at-home convenience for patients and physicians.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Novel Maturation Equation for Hepatic Clearance Across Preterm, Term Neonates, Children, and Adults: Application to Paracetamol and Its Metabolite. 早产儿、足月新生儿、儿童和成人肝脏清除率的新成熟方程：对乙酰氨基酚及其代谢物的应用。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-05 DOI: 10.1002/jcph.70080

Yunjiao Wu, Swantje Völler, Sebastiaan C Goulooze, Karel Allegaert, Catherine M T Sherwin, Anne van Rongen, Daniëlla W E Roofthooft, Sinno H P Simons, Dick Tibboel, Robert B Flint, John N van den Anker, Catherijne A J Knibbe

{"title":"A Novel Maturation Equation for Hepatic Clearance Across Preterm, Term Neonates, Children, and Adults: Application to Paracetamol and Its Metabolite.","authors":"Yunjiao Wu, Swantje Völler, Sebastiaan C Goulooze, Karel Allegaert, Catherine M T Sherwin, Anne van Rongen, Daniëlla W E Roofthooft, Sinno H P Simons, Dick Tibboel, Robert B Flint, John N van den Anker, Catherijne A J Knibbe","doi":"10.1002/jcph.70080","DOIUrl":"https://doi.org/10.1002/jcph.70080","url":null,"abstract":"A preterm and term neonate to adult (PTNA) maturation equation was introduced recently to describe the glomerular filtration rate maturation from birth to adulthood for neonates of varying gestational age. This study aims to evaluate the newly developed PTNA equation against common maturation approaches like allometric scaling (AS0.75), the AS0.75 plus postmenstrual age (PMA)-based Emax (AS0.75 + PMA) equation, and the bodyweight dependent exponent equation (BDE) for the maturation of three hepatic pathways of paracetamol (PCM) from preterm and term neonates up to adults. A population pharmacokinetic analysis was conducted with pooled plasma and urine data of PCM, PCM-glucuronide (PCM-GLU), PCM-sulfate (PCM-SULF), and PCM-oxidative metabolites (PCM-OXI) (number of observations:6428) from 298 subjects, including preterm and term neonates, infants, children, and adults. PTNA, AS0.75, AS0.75 + PMA, and BDE were evaluated separately to describe the formation clearance of each PCM metabolite. Results indicated that the PTNA equation best described the formation clearance of PCM-GLU, outperforming the BDE and AS0.75 + PMA equations in both statistical and graphical evaluation metrics and inter-individual variability reduction. For PCM-SULF and PCM-OXI, the PTNA equation also had the best performance, but the improvements were smaller. The final model described the PK of PCM and its metabolites adequately among subpopulations as indicated by diagnostic plots. In conclusion, the PTNA maturation equation best describes the maturation of all hepatic elimination pathways of PCM. It can, as such, be potentially applied to other drugs and pathways when data from both preterm and term neonates and older children are part of the PK analysis.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

From Genotype to Therapeutic Monitoring: Enhancing Tamoxifen Efficacy in Breast Cancer Treatment. 从基因型到治疗监测：增强他莫昔芬治疗乳腺癌的疗效。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-05 DOI: 10.1002/jcph.70103

Ana Flávia Mendes Batista, Letícia Penteado Petrolli, Maria Paula Marques Pereira, Adriana Rocha, Jurandyr Moreira de Andrade, Vera Lucia Lanchote, João Paulo Bianchi Ximenez

{"title":"From Genotype to Therapeutic Monitoring: Enhancing Tamoxifen Efficacy in Breast Cancer Treatment.","authors":"Ana Flávia Mendes Batista, Letícia Penteado Petrolli, Maria Paula Marques Pereira, Adriana Rocha, Jurandyr Moreira de Andrade, Vera Lucia Lanchote, João Paulo Bianchi Ximenez","doi":"10.1002/jcph.70103","DOIUrl":"https://doi.org/10.1002/jcph.70103","url":null,"abstract":"Endoxifen is the most active metabolite of tamoxifen and plays a central role in its therapeutic efficacy. However, significant interindividual variability in endoxifen plasma concentrations, driven by both genetic and non-genetic factors, may result in subtherapeutic exposure for a substantial subset of patients. This study evaluated the influence of CYP2D6 phenotype and age on endoxifen steady-state concentrations and explored the clinical utility of therapeutic drug monitoring (TDM) to guide tamoxifen therapy. A total of 63 breast cancer patients receiving tamoxifen 20 mg daily for at least 3 months were enrolled. Patients were genotyped for CYP2D6 using TaqMan assays and classified as normal metabolizers (NMs, n = 49), intermediate metabolizers (IMs, n = 13), or ultrarapid metabolizers (UMs, n = 1). Plasma concentrations of tamoxifen and its metabolites were quantified by LC-MS/MS at steady state. Endoxifen levels were significantly lower in IMs (7.13 ng/mL; 95% CI: 3.38-15.08) compared to NMs (22.66 ng/mL; 95% CI: 18.57-27.66; p < .001). Subtherapeutic endoxifen concentrations (<6 ng/mL) were observed in 23.1% of IMs and 4.1% of NMs. These results support the combined use of CYP2D6 genotyping and TDM as the optimal strategy for personalizing tamoxifen therapy and minimizing the risk of subtherapeutic endoxifen exposure.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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