Journal of Clinical Pharmacology最新文献

Population Pharmacokinetics of Alfentanil in Children. 阿芬太尼在儿童体内的群体药代动力学。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-05-16 DOI: 10.1002/jcph.70044

Lorena Medina-Aymerich, Ngoc Betty Ngo, Daniel Gonzalez, Chi D Hornik, Amira Al-Uzri, Rachel G Greenberg, Sarah G Anderson, Elizabeth H Payne, Sitora Turdalieva, Stephen J Balevic

{"title":"Population Pharmacokinetics of Alfentanil in Children.","authors":"Lorena Medina-Aymerich, Ngoc Betty Ngo, Daniel Gonzalez, Chi D Hornik, Amira Al-Uzri, Rachel G Greenberg, Sarah G Anderson, Elizabeth H Payne, Sitora Turdalieva, Stephen J Balevic","doi":"10.1002/jcph.70044","DOIUrl":"https://doi.org/10.1002/jcph.70044","url":null,"abstract":"Alfentanil is an opioid analgesic and anesthetic agent used in surgical procedures. Despite its widespread use in children, the U.S. Food and Drug Administration label lacks specific dosing recommendations for those under 12 years. A population pharmacokinetic analysis was performed using NONMEM (v7.5) to characterize alfentanil's disposition in children. The study included 58 plasma concentrations from 42 patients who received intravenous alfentanil as part of usual care. Median age was 7.57 years (range: 0.33-17.80) and median dosing was 12.5 mcg/kg (range: 4-43). A one-compartment model with first-order elimination best described alfentanil's pharmacokinetics. Among body size measures, total body weight (WT) significantly influenced clearance (CL [L/h]) = 7.42 × (WT/70)0.75) and volume of distribution (V [L]) = 12.6 × (WT/70)1). Inter-individual variability decreased after the inclusion of WT, coefficients of variation were reduced from 104% to 58% and from 169% to 83%, for CL and V, respectively. The final model facilitated simulations to achieve target efficacious analgesic and anesthetic concentrations. For analgesia, an initial 10 mcg/kg bolus (for the first hour) followed by an 8 mcg/kg/h infusion (starting at 1 h) achieved the efficacious targeted concentrations (10-100 ng/mL). For procedures that typically require minimal or moderate sedation, a 25 mcg/kg bolus followed by a 20 mcg/kg/h infusion (starting at 5 min) achieved the targeted concentrations (50-200 ng/mL, depending on the procedure). These regimens should be prospectively evaluated to ensure their safety and confirm their efficacy. Overall, this study provides valuable insights into pharmacokinetics and dosing of alfentanil in children.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081402","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

Dextromethorphan versus Dextrorphan: A Quantitative Comparison of Antitussive Potency following Separate Administration of Metabolite. 右美沙芬与右美沙芬：代谢物单独给药后镇咳效力的定量比较。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-05-16 DOI: 10.1002/jcph.70049

Saeed Rezaee, Caroline E Wright, Alyn H Morice, Amin Rostami-Hodjegan

{"title":"Dextromethorphan versus Dextrorphan: A Quantitative Comparison of Antitussive Potency following Separate Administration of Metabolite.","authors":"Saeed Rezaee, Caroline E Wright, Alyn H Morice, Amin Rostami-Hodjegan","doi":"10.1002/jcph.70049","DOIUrl":"https://doi.org/10.1002/jcph.70049","url":null,"abstract":"To assess the antitussive effects of dextrorphan (DOR) relative to its parent compound, dextromethorphan (DEX) a double-blind, randomized, placebo-controlled crossover study was conducted in 23 healthy volunteers using citric acid cough challenge test after administering placebo, DEX, or DOR. Plasma concentrations and cough frequency were monitored over 24 h, followed by model independent analysis and pharmacokinetic-pharmacodynamic (PKPD) modelling to discern the relative potency of each moiety. Model-independent pairwise analysis of the area under the effect curve (AUEC₀₋₂₄ h) showed no significant difference between DOR, DEX, and placebo's antitussive effects (p > .06), indicating the influence of considerable inter-individual variability and the need for larger sample sizes. The model-based analysis established DOR's relative potency at 26% compared to DEX, with maximum cough inhibition of 23% and IC50 of 0.3 ng/mL. PKPD measures were more accurate for DEX than DOR, particularly at lower baseline cough counts. In conclusion, while DOR retains some antitussive potency, since it is substantially less potent than DEX, higher relative concentrations are required to reach the same effect. Although separate administration of metabolite on its own is considered gold standard to establish its relative potency compared to parent compound, the variability in effect may prevent clear demonstration of effects without modelling particularly when these take benefit of the perturbing the balance of parent/metabolite ratios (e.g. via inhibition) or using the natural variational of such ratios in different individuals.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081398","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

Effects of Hepatic or Renal Impairment on Pharmacokinetics of Fruquintinib. 肝脏或肾脏损害对氟喹替尼药代动力学的影响。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-05-10 DOI: 10.1002/jcph.70040

Martha Gonzalez, Zhao Yang, William Schelman, Thomas C Marbury, Juan C Rondon, William Smith, Xiaofei Zhou, Neeraj Gupta, Caly Chien

{"title":"Effects of Hepatic or Renal Impairment on Pharmacokinetics of Fruquintinib.","authors":"Martha Gonzalez, Zhao Yang, William Schelman, Thomas C Marbury, Juan C Rondon, William Smith, Xiaofei Zhou, Neeraj Gupta, Caly Chien","doi":"10.1002/jcph.70040","DOIUrl":"https://doi.org/10.1002/jcph.70040","url":null,"abstract":"Fruquintinib (FRUZAQLATM) is a highly selective tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors (-1, -2, and -3). Two Phase 1, open-label, single-dose studies investigated the impact of hepatic or renal impairment on the pharmacokinetics and tolerability of fruquintinib. Participants with moderate renal impairment (creatinine clearance [CrCl] 30-59 mL/min; eight participants) and matched healthy controls (eight participants for each study) received fruquintinib 5 mg. Participants with moderate hepatic impairment (Child-Pugh B; eight participants) and severe renal impairment (CrCl 15-29 mL/min; eight participants) received fruquintinib 2 mg. Pharmacokinetic samples were collected over 240 h. Fruquintinib pharmacokinetics were similar between participants with moderate hepatic impairment and healthy controls; geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum plasma concentration (Cmax), area under the plasma concentration-time curve from 0 to time of last measurable concentration (AUC0-t), and AUC from 0 to infinity (AUC0-inf) were 1.04 (0.87-1.24), 0.89 (0.64-1.23), and 0.91 (0.66-1.26), respectively. Fruquintinib pharmacokinetics were similar between participants with severe or moderate renal impairment and healthy controls. Compared with healthy controls, the respective GMRs (90% CIs) for Cmax, AUC0-t, and AUC0-inf for participants with severe renal impairment were 0.89 (0.78-1.03), 0.97 (0.83-1.14), and 1.01 (0.85-1.19), and for participants with moderate renal impairment were 0.95 (0.78-1.15), 1.06 (0.89-1.26), and 1.07 (0.89-1.28). Fruquintinib was generally well tolerated. These results support fruquintinib use without dose adjustment (5 mg daily, 3 weeks on, and 1 week off) in patients with moderate hepatic impairment or moderate to severe renal impairment.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046496","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 Nicotine Pharmacokinetics of Nicotine Pouches Under Naturalistic Use Conditions. 基于生理的药代动力学模型预测自然使用条件下尼古丁袋的药代动力学。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-05-10 DOI: 10.1002/jcph.70038

Ali Salehi, Mohamadi A Sarkar, Jennifer H Smith, Ali A Rostami

{"title":"Physiologically Based Pharmacokinetic Modeling to Predict Nicotine Pharmacokinetics of Nicotine Pouches Under Naturalistic Use Conditions.","authors":"Ali Salehi, Mohamadi A Sarkar, Jennifer H Smith, Ali A Rostami","doi":"10.1002/jcph.70038","DOIUrl":"https://doi.org/10.1002/jcph.70038","url":null,"abstract":"Adult users of traditional tobacco products like combustible cigarettes (CC) or moist smokeless tobacco (MST) products can reduce exposure to toxicants by switching to potentially less harmful alternatives such as tobacco-free nicotine pouches (NP). Nicotine exposure assessment is an important consideration to determine the switching potential of NPs. These measurements are often conducted using randomized clinical studies. However, characterizing nicotine exposure under real-world use conditions can further inform these assessments. We propose a framework based on physiologically based pharmacokinetic (PBPK) modeling that integrates typical use patterns and clinical pharmacokinetic (PK) data to predict nicotine exposure under actual use conditions. A tissue permeation model precedes the PBPK modeling and is characterized by two physiological parameters, nicotine diffusivity, and effective tissue thickness, which were determined and validated using literature data. A product-specific tissue uptake fraction was determined by regression of nicotine pharmacokinetics measured under controlled use conditions and applied consistently for alternative use scenario analyses. Nicotine PK profiles were predicted under various use scenarios for cigarette smoking or MST use and compared to that from the use of two NPs, namely on!® and on! PLUS™ NPs (Test Products). The nicotine PK parameters predicted under real-world use conditions were not higher for Test Products relative to cigarettes or MST. The proposed modeling here can further inform nicotine exposure under actual use conditions. PBPK modeling can be a fit-for-purpose tool for predicting nicotine exposure under various use scenarios.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144054942","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

Can Methotrexate Monotherapy Achieve Clinical Remission in Patients with Active Rheumatoid Arthritis? A Model-Based Meta-Analysis. 甲氨蝶呤单药治疗活动性类风湿关节炎能否获得临床缓解？基于模型的元分析。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-05-06 DOI: 10.1002/jcph.70039

Shengyang Chen, Yangrui Wu, Wei Huang, Jianxing Zhou, Zipeng Wei, Xuemei Wu

{"title":"Can Methotrexate Monotherapy Achieve Clinical Remission in Patients with Active Rheumatoid Arthritis? A Model-Based Meta-Analysis.","authors":"Shengyang Chen, Yangrui Wu, Wei Huang, Jianxing Zhou, Zipeng Wei, Xuemei Wu","doi":"10.1002/jcph.70039","DOIUrl":"https://doi.org/10.1002/jcph.70039","url":null,"abstract":"This study utilized model-based meta-analysis (MBMA) to systematically assess the efficacy of methotrexate (MTX) monotherapy in improving rheumatoid arthritis (RA) symptoms and function. The assessment was based on indicators such as Disease Activity Score 28 (DAS28), Health Assessment Questionnaire, and American College of Rheumatology (ACR) criteria. Additionally, the study investigated the impact of dosage, disease duration, and serum markers-C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)-on treatment efficacy. A systematic review of randomized controlled trials yielded data from 69 studies involving 7999 patients. Efficacy models for DAS28, ACR20, and ACR50 were developed to explore the impact of time and dosage, with simulations conducted to predict outcomes at 12 weeks. Results showed that the maximum reduction in DAS28 (Emax) was -54.90% (RSE: 13%), with an ET50 of 20.6 weeks (RSE: 26%). For ACR20 and ACR50, Emax values were 70.3% (RSE: 3%) and 49.4% (RSE: 24%), with ET50s of 6.69 (RSE: 7%) and 27.3 (RSE: 37%) weeks, respectively. Neither dosage nor patient-specific factors like disease duration, CRP, or ESR significantly influenced efficacy. MTX is effective in the early treatment of RA but often fails to achieve remission in patients.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026592","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 Physiologically Based Modeling Approach to Evaluate Intravenous Levetiracetam Dosing in Term and Preterm Neonates. 一种基于生理学的建模方法来评估足月和早产儿静脉注射左乙拉西坦的剂量。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-05-02 DOI: 10.1002/jcph.70037

Alexis Johnson, Nolan Thomas, Max Blumenthal, Chrysanthy Ikonomidou, Sin Yin Lim

{"title":"A Physiologically Based Modeling Approach to Evaluate Intravenous Levetiracetam Dosing in Term and Preterm Neonates.","authors":"Alexis Johnson, Nolan Thomas, Max Blumenthal, Chrysanthy Ikonomidou, Sin Yin Lim","doi":"10.1002/jcph.70037","DOIUrl":"https://doi.org/10.1002/jcph.70037","url":null,"abstract":"Seizures are the most common neurologic emergency in neonates and are associated with significant morbidity and mortality. Current first-line pharmacotherapy, phenobarbital, is associated with serious adverse effects, including impairment of the developing brain. Levetiracetam is a well-tolerated alternative; however, its use is limited because its optimal dosing in neonates remains unknown. Additionally, limited knowledge of levetiracetam pharmacokinetics in neonates, especially preterm neonates, means they generally receive the same weight-based dosing. This may put preterm neonates at risk of increased adverse events or insufficient drug effects. This study developed a physiologically based pharmacokinetic (PBPK) model for levetiracetam in term and preterm neonates to evaluate their pharmacokinetic differences. After accounting for the physiological changes, a 1.56-fold increase in drug tissue distribution was needed to represent the increased volume of distribution of levetiracetam in neonates. In term neonates, scaling renal clearance from children based on estimated glomerular filtration rate required a 61% increase to accurately describe renal clearance. Additionally, allometric scaling to extrapolate metabolic clearance required age-dependent corrections to account for the reduced metabolic clearance. In preterm neonates, extrapolated renal clearance was approximately equal to observed total clearance, suggesting renal clearance as the sole elimination route. Consistently, predicted metabolic clearance approached zero when the postmenstrual age was <37.5 weeks. Our simulations showed that common intravenous levetiracetam dosing regimens resulted in higher plasma concentrations in more premature neonates or those with reduced kidney function. In preterm neonates, these regimens may result in plasma concentrations exceeding toxicity thresholds, indicating a need for lower weight-based dosing.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991592","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 Systematic Evaluation of the Dosing Regimens for Approved Targeted Therapies and Immune Checkpoint Inhibitors in Metastatic Renal Cell Carcinoma From a Project OPTIMUS Perspective. 从OPTIMUS项目的角度对转移性肾细胞癌批准的靶向治疗和免疫检查点抑制剂的给药方案进行系统评估。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-05-02 DOI: 10.1002/jcph.70035

Zhiyuan Tan, Swantje Völler, Aymara Sancho-Araiz, Catherijne A J Knibbe, Dirk Jan A R Moes

{"title":"A Systematic Evaluation of the Dosing Regimens for Approved Targeted Therapies and Immune Checkpoint Inhibitors in Metastatic Renal Cell Carcinoma From a Project OPTIMUS Perspective.","authors":"Zhiyuan Tan, Swantje Völler, Aymara Sancho-Araiz, Catherijne A J Knibbe, Dirk Jan A R Moes","doi":"10.1002/jcph.70035","DOIUrl":"https://doi.org/10.1002/jcph.70035","url":null,"abstract":"Targeted therapies and immune checkpoint inhibitors (ICIs) have significantly improved survival outcomes in metastatic renal cell carcinoma (mRCC) but are often associated with high rates of adverse events, leading to dose reductions or treatment discontinuation. The FDA's recent initiative, Project OPTIMUS, emphasizes the importance of optimizing dosing regimens in oncology clinical development, and moves beyond the conventional maximum tolerated dose approach. In this study, we aimed to review and redefine the approved dosing strategies for targeted therapies and ICIs in mRCC from the Project OPTIMUS perspective, including pazopanib, axitinib, cabozantinib, sunitinib, everolimus, and nivolumab. A comprehensive summary of FDA clinical pharmacology reviews and clinical studies performed in routine clinical practice was conducted, alongside model-informed simulations of pharmacokinetic profiles with approved and alternative regimens. Results demonstrated that actual tolerated doses in clinical practice were 46.1% to 86% lower than the approved dosages, with up to 75% of patients requiring dose adjustments. Model-informed simulations suggested that for most targeted therapies, a 14%-50% dose reduction maintained comparable efficacy while improving tolerability. For nivolumab, simulations confirmed adequate drug exposure with the approved flat dose regimens, without an increase of adverse effects. In conclusion, we identified optimized dosing regimens that could improve drug tolerability while maintaining efficacy for approved targeted therapies and ICIs in mRCC. We suggest that these optimized dosing regimens should be considered for use in clinical practice and that the optimal exposure range be included in drug labels to support pharmacokinetically guided dose individualization in clinical practice.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065158","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

Optimizing Zanubrutinib Dosing in Patients: A PBPK-BO Model Approach to Drug-Drug Interactions and Patients with Hepatic Impairment. 优化患者的扎鲁替尼剂量：药物-药物相互作用和肝功能损害患者的PBPK-BO模型方法。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-30 DOI: 10.1002/jcph.70042

Jiawei Ren, Dan Shan, Guijuan Yue, Qiang He

{"title":"Optimizing Zanubrutinib Dosing in Patients: A PBPK-BO Model Approach to Drug-Drug Interactions and Patients with Hepatic Impairment.","authors":"Jiawei Ren, Dan Shan, Guijuan Yue, Qiang He","doi":"10.1002/jcph.70042","DOIUrl":"https://doi.org/10.1002/jcph.70042","url":null,"abstract":"This study aimed to develop a physiologically based pharmacokinetic and Bruton's tyrosine kinase (BTK) occupancy (PBPK-BO) model to evaluate the pharmacokinetics (PK) and BTK occupancy (BO) of zanubrutinib (ZAN), particularly in relation to drug-drug interactions (DDIs) involving cytochrome P450 3A4 (CYP3A4) modulators and for patients with hepatic impairment. Population PBPK-BO and DDI models for ZAN were constructed using physicochemical properties, pharmacokinetic data, BTK occupancy levels, and physiological parameters. The PBPK-BO model was validated against clinically measured PK, DDI, and BO data, demonstrating accurate predictions of ZAN's plasma concentration and the time-course profiles of BO. The predicted ratios of AUC and Cmax in patients consistently fell within the acceptable range of 1.5-fold. The predicted fold-change ratios in DDIs and in patients with hepatic impairment also are in good agreement with the observed data. These findings confirm the reliability of the PBPK-BO model for predicting PK and BO of ZAN. Based on the model with >95% BO as a clinical efficacy threshold, the recommended dosing of ZAN should be reduced to 40 mg once daily (OD) when used with strong CYP3A4 inhibitors such as itraconazole or clarithromycin. For moderate CYP3A4 inhibitors like fluconazole, dosing should be adjusted to either 160 mg OD or 80 mg twice daily (BID). Additionally, the model advises against concomitant administration of ZAN with strong CYP3A4 inducers such as rifampicin or moderate inducers like rifabutin. Furthermore, the PBPK-BO model suggests that dosing regimens should be reduced to 80 mg BID or 160 mg OD in patients with severe hepatic impairment. The PBPK-BO model provides a robust framework for clinical decision-making, aimed at optimizing treatment outcomes in patients receiving ZAN therapy.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036053","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

First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Oral Complement Factor D Inhibitor BCX9930 in Healthy Participants. 口服补体因子D抑制剂BCX9930在健康参与者中的安全性、耐受性、药代动力学和药效学的首次人体研究

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-28 DOI: 10.1002/jcph.70032

Matthew Davidson, Xilin Chen, Amanda Mathis, Sylvia Dobo, Melanie Cornpropst, Fugang Zhu, Cynthia Parker, David Reynolds, Yarlagadda S Babu, Stuart Mair, William P Sheridan

{"title":"First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Oral Complement Factor D Inhibitor BCX9930 in Healthy Participants.","authors":"Matthew Davidson, Xilin Chen, Amanda Mathis, Sylvia Dobo, Melanie Cornpropst, Fugang Zhu, Cynthia Parker, David Reynolds, Yarlagadda S Babu, Stuart Mair, William P Sheridan","doi":"10.1002/jcph.70032","DOIUrl":"https://doi.org/10.1002/jcph.70032","url":null,"abstract":"BCX9930 is a potent, selective oral inhibitor of complement Factor D that inhibits the activation of the complement alternative pathway (AP) and has the potential for treatment of complement-mediated diseases. This was a first-in-human, randomized, double-blind, placebo-controlled study that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of BCX9930 in healthy participants. Safety and tolerability were evaluated via clinical and laboratory monitoring. Plasma concentrations of BCX9930 were measured using validated liquid chromatography-dual mass spectrometry; PD effects were assessed via multiple assays. Participants were enrolled into seven single dose cohorts (10-2000 mg) and eight multiple-dose cohorts (50-500 mg every 12 h [Q12h] and 1000-2000 mg every 24 h [Q24h]). Enrollment comprised 152 participants (122 received BCX9930 and 30 received placebo). Following BCX9930 administration, plasma exposure was approximately dose proportional across all doses. The effective half-life (t1/2) ranged from 6.45 to 7.75 h for Q12h doses at steady state. Clearance and times to maximum concentration (Tmax) were similar across all doses studied, without evidence of dose- or time-dependent clearance. BCX9930 administration resulted in rapid, potent, and dose-dependent AP inhibition. Doses ≥200 mg Q12h and ≥1000 mg Q24h achieved maximal suppression (>98% relative to baseline levels) of AP activity over the full dosing interval. No clinically significant dose-related trends in adverse events (AEs), laboratory values, vital signs, or electrocardiograms were noted. BCX9930 was safe and generally well tolerated in this first-in-human study and displayed highly favorable PK and PD profiles. These results support Factor D inhibition as a promising strategy for treatment of complement-mediated diseases.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020526","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

Expansion of a Pharmacokinetic Model for Diazepam to Characterize Real-World IV and Oral Data in Children With and Without Obesity. 扩展地西泮的药代动力学模型，以表征患有和非肥胖儿童的静脉注射和口服数据。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-28 DOI: 10.1002/jcph.70027

Sean M McCann, Jiali Wen, Stephen J Balevic, William J Muller, Amira Al-Uzri, Chi D Hornik, Marisa L Meyer, Sarah G Anderson, Elizabeth H Payne, Sitora Turdalieva, James M Chamberlain, Daniel Gonzalez

{"title":"Expansion of a Pharmacokinetic Model for Diazepam to Characterize Real-World IV and Oral Data in Children With and Without Obesity.","authors":"Sean M McCann, Jiali Wen, Stephen J Balevic, William J Muller, Amira Al-Uzri, Chi D Hornik, Marisa L Meyer, Sarah G Anderson, Elizabeth H Payne, Sitora Turdalieva, James M Chamberlain, Daniel Gonzalez","doi":"10.1002/jcph.70027","DOIUrl":"https://doi.org/10.1002/jcph.70027","url":null,"abstract":"Diazepam is a benzodiazepine approved for use in adults and children. The label incorporates recommended dosing for status epilepticus in children. Published population pharmacokinetic (PK) modeling recommends an intravenous bolus dose of 0.2 mg/kg capped at 8 mg to reach the suggested target exposure of 200-600 ng/mL at 10 min post dose in children up to 17 years of age. This model was developed for children generally without obesity based on IV data, and it is unclear how increased body weight may affect exposure or target attainment given capped dosing. Diazepam concentrations after IV or oral administration for 61 children aged 2.5 to 20.6 years were used to externally evaluate the model including the addition of fixed oral absorption parameters. Then, PK parameters were re-estimated with the external population alone and again in combination with the original population. Re-estimated parameters from the combined population were used to simulate recommended dosing for children with and without obesity. The external dataset included 88 plasma concentrations from 61 children (54 with obesity) receiving diazepam per standard of care. The external evaluation resulted in 34.5% of predicted values within 30% of the observed concentration. Parameter re-estimation resulted in increased central volume of distribution (26% increase from a previous model), reduced peripheral volume of distribution and intercompartmental clearance, and similar clearance estimates. Simulations demonstrated that dosing caps may prevent children with obesity from reaching the suggested target exposure that is recommended for the treatment of status epilepticus. Further study is needed to evaluate the target exposure range in this population.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988924","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