Journal of Clinical Pharmacology最新文献

Risks and Benefits for Sirolimus in Aging Prevention. 西罗莫司预防衰老的风险和益处。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-10-09 DOI: 10.1002/jcph.70112

Mallikaarjun S, Kirstein M N, Gupta A K, Shukla S, Gromme A N

引用次数: 0

Quantitative Comparison of the Predictive Accuracy of Warfarin Pharmacogenetic Dosing Algorithms Derived From Population Data of Different Ethnicities in the Chinese Population. 基于中国不同种族人群数据的华法林药物遗传给药算法预测准确性的定量比较。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-10-04 DOI: 10.1002/jcph.70118

Dongyun Nan, Shaoke Li, Yi Wang, Yiqun Cai, Bo Liu, Jialing Peng, Jiexin Deng

{"title":"Quantitative Comparison of the Predictive Accuracy of Warfarin Pharmacogenetic Dosing Algorithms Derived From Population Data of Different Ethnicities in the Chinese Population.","authors":"Dongyun Nan, Shaoke Li, Yi Wang, Yiqun Cai, Bo Liu, Jialing Peng, Jiexin Deng","doi":"10.1002/jcph.70118","DOIUrl":"https://doi.org/10.1002/jcph.70118","url":null,"abstract":"This study systematically evaluated the predictive performance of 10 international warfarin dosing algorithms (originating from the United States, China, Singapore, Thailand, India, United Kingdom, Japan, and South Korea) in 87 Chinese patients, aiming to identify optimal algorithms for warfarin dose optimization. Clinical and genetic data were analyzed using mean dose error (MDE) and ideal dose prediction (IDP) rate metrics, with sensitivity analysis stratifying patients into low-dose (≤14 mg/week, n = 21), medium-dose (14-21 mg/week, n = 43), and high-dose (≥21 mg/week, n = 23) groups based on actual weekly maintenance dose (mean: 18.9 ± 8.8 mg/week). Results revealed significant variation in MDEs (-6.6 to 11.3 mg/week) across algorithms. The Chinese-developed Huang algorithm and Thai-developed Sangviroon algorithm demonstrated superior overall accuracy, both achieving MDEs <1 mg/week and IDPs >40%. In medium-dose patients, their performance was particularly robust (Huang IDP: 65.1%; Sangviroon IDP: 74.4%). However, both algorithms showed limitations at dose extremes: they overestimated doses in 90.48% of low-dose patients and underestimated doses in 60.9%-65.2% of high-dose patients. This evidence indicates that region-specific algorithms (Huang and Sangviroon) outperform internationally recommended models (e.g., IWPC/Gage endorsed by CPIC) for warfarin dosing in Chinese populations. Locally derived algorithms may thus offer greater clinical utility despite current international guidelines.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226127","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 Dapoxetine in Healthy Chinese Male Subjects. 达泊西汀在中国健康男性人群中的药代动力学。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-10-01 DOI: 10.1002/jcph.70117

Libin Pu, Tong Wu, Fuqiang Bai, Haobo Lu, Yiming Wang, Yuan Gao, Wen Qiu

{"title":"Population Pharmacokinetics of Dapoxetine in Healthy Chinese Male Subjects.","authors":"Libin Pu, Tong Wu, Fuqiang Bai, Haobo Lu, Yiming Wang, Yuan Gao, Wen Qiu","doi":"10.1002/jcph.70117","DOIUrl":"https://doi.org/10.1002/jcph.70117","url":null,"abstract":"Dapoxetine is a short-acting selective serotonin reuptake inhibitor used to treat premature ejaculation. However, its clinical effectiveness is challenged by substantial inter-individual variability in pharmacokinetics, as both the drug's therapeutic efficacy and the incidence of adverse reactions are highly dependent on its exposure. This study aims to develop a population pharmacokinetic model for dapoxetine, to investigate the sources of the variability, and to identify demographic and pharmacogenetic factors that influence drug exposure. The pharmacokinetic data for this analysis were obtained from a bioequivalence study conducted in 39 healthy Chinese male subjects. As part of this study, all volunteers were genotyped for the CYP3A4*1G, CYP3A5*3, CYP2D6*10, and CYP2D6*41 allelic variants. Population pharmacokinetic modeling was performed in Monolix. The final model was then used to simulate and compare the effect of different covariate levels on dapoxetine exposure. A two-compartment model with first-order absorption and an absorption lag time best described the pharmacokinetics of dapoxetine. The population parameters for apparent clearance (CL/F), apparent intercompartmental clearance (Q/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption lag time (Tlag), and absorption rate constant (ka) were 37.8 L/h, 17.2 L/h, 65.6 L, 191.7 L, 0.68 h, and 1.29/h, respectively. CYP2D6*10 and CYP2D6*41 alleles were found to be significant covariates on CL/F. The CYP3A4*1G allele influenced Q/F, while body mass index (BMI) was a significant covariate on Vc/F. Our analysis identified CYP2D6*10 and CYP2D6*41 polymorphisms as the significant factors contributing to inter-individual variability and influencing drug exposure.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201445","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

Caffeine in Preterm Infants and its Effect on Neonatal Sleep: A Systematic Review. 早产儿咖啡因及其对新生儿睡眠的影响：一项系统综述。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-29 DOI: 10.1002/jcph.70096

Kristina Denisova, Nicholas Diamandis, Jean Ee Tang, Mia Eng-Kohn, Gloria Willson, Bikash Shrestha, Alyssa DeStefano, Jane Lee, Jacob Merrin, Zhichun Lin, Neli Kotlyar, Amanda Kessler, Ryan Dosumu-Johnson, Kirwan Walsh, Yidan Lou, Jeremy Payano, John N van den Anker

{"title":"Caffeine in Preterm Infants and its Effect on Neonatal Sleep: A Systematic Review.","authors":"Kristina Denisova, Nicholas Diamandis, Jean Ee Tang, Mia Eng-Kohn, Gloria Willson, Bikash Shrestha, Alyssa DeStefano, Jane Lee, Jacob Merrin, Zhichun Lin, Neli Kotlyar, Amanda Kessler, Ryan Dosumu-Johnson, Kirwan Walsh, Yidan Lou, Jeremy Payano, John N van den Anker","doi":"10.1002/jcph.70096","DOIUrl":"https://doi.org/10.1002/jcph.70096","url":null,"abstract":"The development of good-quality sleep is very important in early life. Sleep promotion programs aim to increase preterm infants' sleep quality because preterm infants in the neonatal intensive care unit (NICU) have poor sleep. Interestingly, the majority of preterm infants are treated with caffeine, a nervous system stimulant. The primary objective of this systematic review was therefore to appraise the current evidence concerning potentially sleep-disruptive effects of caffeine in preterm infants within the first month of life. We performed a search (PROSPERO protocol CRD42022273596) according to PRISMA guidelines in PubMed, Embase, Scopus, and PsycInfo (as well as CENTRAL). We looked for studies involving preterm infants (<37 weeks of gestational age) treated with caffeine in the NICU, with sleep measures acquired within the first month of life. Eight studies met the eligibility criteria. Underlying effect sizes for main outcomes are represented using albatross plots. Among studies reporting on wakefulness (N = 213), 83.33% detected significant disruptions (P < .05). Among studies reporting on sensorimotor functioning (N = 80), 100% detected significant reductions (P < .05). Moreover, significant reductions (P < .05) in sleep states were detected. Available evidence suggests that caffeine exposure in preterm infants may produce alterations in sleep-wake and sensorimotor functioning, and related processes during the first month of life. The overall evidence is mixed, with some studies reporting no effect of caffeine exposure on neonatal sleep. Additional research is needed to understand how caffeine alters the quality of neonatal sleep in preterm infants and whether the effects may differ among infant subgroups. There is a continued need to investigate and support sleep quality in preterm infants during their NICU stay.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187409","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 Oxcarbazepine to Characterize Its Disposition in Children with Obesity. 奥卡西平在肥胖儿童中的生理药代动力学建模。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-29 DOI: 10.1002/jcph.70107

Patricia D Maglalang, Jaydeep Sinha, Victόria Etges Helfer, Andrea Edginton, Kanecia Zimmerman, Chi Dang Hornik, William J Muller, Mobeen Rathore, Daniel K Benjamin, Jia-Yuh Chen, Ravinder Anand, Daniel Gonzalez

{"title":"Physiologically Based Pharmacokinetic Modeling of Oxcarbazepine to Characterize Its Disposition in Children with Obesity.","authors":"Patricia D Maglalang, Jaydeep Sinha, Victόria Etges Helfer, Andrea Edginton, Kanecia Zimmerman, Chi Dang Hornik, William J Muller, Mobeen Rathore, Daniel K Benjamin, Jia-Yuh Chen, Ravinder Anand, Daniel Gonzalez","doi":"10.1002/jcph.70107","DOIUrl":"10.1002/jcph.70107","url":null,"abstract":"Oxcarbazepine (OXC) is a second-generation antiseizure medication, effective through its active metabolite, 10-mono-hydroxy derivative (MHD). OXC is used as adjunctive therapy for focal-onset and primary generalized tonic-clonic seizures, with recommended dosing based on age and body weight. This study uses physiologically based pharmacokinetic (PBPK) modeling and leverages pharmacokinetic (PK) data acquired from children enrolled in pragmatic trials to understand dosing and subsequent exposure requirements in children with obesity. Drug concentrations of OXC and MHD (n = 148 each) from children with (n = 31) and without (n = 10) obesity, aged 2-20 years, were collected from two clinical trials (NCT01431326 and NCT02993861) and used for external evaluation of a previously developed PBPK model of OXC using PK-Sim. We used a previously published virtual population that accounts for the obesity-related changes in physiology (e.g., liver size and glomerular filtration rate) in children for PK simulations in children with obesity. Model evaluation showed that ≥80% of MHD concentrations contributed by about two thirds of study subjects (26 out of 41) fell within the 90% prediction interval. The PBPK model showed that children with obesity had lower median (interquartile range) simulated weight-normalized clearance (0.060 L/h/kg [0.048-0.076 L/h/kg]) than children without obesity (0.067 L/h/kg [0.060-0.077 L/h/kg]). Simulations revealed that the recommended pediatric dosing regimen produced comparable MHD exposure between children with and without obesity at steady state, supporting its applicability regardless of obesity status. This PBPK-based dosing aligns with product label recommendations and demonstrates the potential of PBPK modeling for dosing other drugs in children with obesity.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Approval of Upadacitinib in Pediatric Patients with Active Polyarticular Juvenile Idiopathic Arthritis or Active Psoriatic Arthritis: A Regulatory Perspective. 批准Upadacitinib用于活动性多关节幼年特发性关节炎或活动性银屑病关节炎的儿科患者：调节角度

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-27 DOI: 10.1002/jcph.70104

Lei He, Da Zhang, Eric J Gapud, Suzette Peng, Ozlem Belen, Chandrahas Sahajwalla, Suresh Doddapaneni, Youwei Bi, Jianmeng Chen

{"title":"Approval of Upadacitinib in Pediatric Patients with Active Polyarticular Juvenile Idiopathic Arthritis or Active Psoriatic Arthritis: A Regulatory Perspective.","authors":"Lei He, Da Zhang, Eric J Gapud, Suzette Peng, Ozlem Belen, Chandrahas Sahajwalla, Suresh Doddapaneni, Youwei Bi, Jianmeng Chen","doi":"10.1002/jcph.70104","DOIUrl":"https://doi.org/10.1002/jcph.70104","url":null,"abstract":"On April 26, 2024, FDA approved Rinvoq (upadacitinib, extended-release [ER] tablets) and Rinvoq LQ (1 mg/mL oral solution), a new pediatric immediate-release (IR) formulation, for the treatment of active polyarticular juvenile idiopathic arthritis (pJIA) and active psoriatic arthritis (PsA) in patients 2 years of age and older. The approved dosing regimens include a weight-tiered twice daily (BID) regimen with IR oral solution and a once-daily (QD) regimen with ER tablets. The objective of this article is to summarize the FDA's major review findings and considerations supporting these approvals from a regulatory perspective. This clinical development program included a single study (Study 1) conducted in pediatric subjects aged 2 to less than 18 years with JIA with active polyarthritis to evaluate the pharmacokinetics (PK), safety, and tolerability of multiple doses of upadacitinib. No clinical trials or dedicated PK studies were conducted in pediatric patients with PsA. Efficacy was extrapolated from adults with rheumatoid arthritis (RA) or PsA to pediatric patients with pJIA or PsA, respectively, based on a PK-matching approach considering disease similarity, similar response to treatment, and comparable PK exposure. PK data analysis and simulations showed that the approved upadacitinib pediatric dosing regimen, including a BID regimen with IR oral solution and QD regimen with ER tablet, provide comparable PK exposure (Cmax and AUC) in pediatric subjects with pJIA or PsA as compared to the approved 15 mg ER tablet QD regimen in adults with RA or PsA, respectively, supporting the efficacy extrapolation from adults to pediatric subjects.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182432","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

Evaluation of the Pharmacokinetics, Disposition, and Metabolism of Miricorilant, a Novel Glucocorticoid Receptor Modulator for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis in Nonclinical and Clinical Studies. Miricorilant是一种治疗代谢功能障碍相关脂肪性肝炎的新型糖皮质激素受体调节剂，在非临床和临床研究中对其药代动力学、处置和代谢的评估。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-27 DOI: 10.1002/jcph.70113

Hazel J Hunt, Kirsteen M Donaldson, Jeevan R Kunta, Joseph M Custodio

{"title":"Evaluation of the Pharmacokinetics, Disposition, and Metabolism of Miricorilant, a Novel Glucocorticoid Receptor Modulator for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis in Nonclinical and Clinical Studies.","authors":"Hazel J Hunt, Kirsteen M Donaldson, Jeevan R Kunta, Joseph M Custodio","doi":"10.1002/jcph.70113","DOIUrl":"https://doi.org/10.1002/jcph.70113","url":null,"abstract":"Miricorilant is a novel selective glucocorticoid receptor (GR) modulator with mixed agonist/antagonist effects at the GR and modest antagonism at the mineralocorticoid receptor that is being developed for the treatment of metabolic dysfunction-associated steatohepatitis. Its overall pharmacokinetic characteristics were assessed, including its disposition (absorption, distribution, metabolism, and elimination [ADME]) and drug-drug interaction (DDI) potential. In vitro, miricorilant (1) demonstrated >99% plasma protein binding in mice, rats, monkeys, and humans, (2) was a modest inhibitor of CYP3A4, CYP2C8, CYP2C9, UGT1A1, and a strong inhibitor of BCRP, (3) was predominantly metabolized by CYP2C19 (≈94%), and (4) showed no induction potential for CYP1A2 and CYP2B6, but showed a concentration-dependent induction of CYP3A4 (6.5-fold) in 1 out of 3 donors tested. In a tissue distribution study in mice, miricorilant was distributed with high levels of radioactivity present in several tissues, including the liver. In animal and human ADME studies, the majority of total radioactivity was recovered in feces (>78%) versus urine (<5%), suggesting hepatic elimination with minor contribution of renal elimination. In phase 1 clinical studies in healthy subjects, miricorilant showed an approximately dose-proportional increase in systemic exposure in the dose range 100-900 mg with an elimination half-life of ≈20 h. In clinical DDI studies at the total plasma concentrations evaluated, miricorilant was a strong inhibitor of CYP2C8 and a moderate inhibitor of BCRP with no meaningful inhibition of CYP2C9, CYP3A4, or UGT1A1, and a moderately sensitive substrate of CYP2C19. Miricorilant was safe and well-tolerated in the phase 1 studies.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145179704","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

In Vitro and Clinical Evaluation of Potential Interactions of Bemnifosbuvir with Drug Transporters. 贝尼非布韦与药物转运体潜在相互作用的体外和临床评价。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-27 DOI: 10.1002/jcph.70114

Xiao-Jian Zhou, Alex Vo, Gaetano Morelli, Maureen Montrond, Shannan Lynch, Keith Pietropaolo, Bruce Belanger, Arantxa Horga, Nancy Agrawal, Janet Hammond

{"title":"In Vitro and Clinical Evaluation of Potential Interactions of Bemnifosbuvir with Drug Transporters.","authors":"Xiao-Jian Zhou, Alex Vo, Gaetano Morelli, Maureen Montrond, Shannan Lynch, Keith Pietropaolo, Bruce Belanger, Arantxa Horga, Nancy Agrawal, Janet Hammond","doi":"10.1002/jcph.70114","DOIUrl":"https://doi.org/10.1002/jcph.70114","url":null,"abstract":"Bemnifosbuvir is a novel oral guanosine nucleotide prodrug candidate for the treatment of chronic hepatitis C virus infection. Potential drug-drug interactions (DDIs) of bemnifosbuvir as a substrate or perpetrator with regard to ATP-binding cassette (ABC) and solute carrier (SLC) transporters were evaluated in vitro and in clinical studies. Bemnifosbuvir was demonstrated in vitro as a substrate and inhibitor of the ABC transporters' P-glycoprotein (P-gp), as an inhibitor of the breast cancer resistance protein (BCRP), as well as a weak inhibitor of SLC transporters, including organic anion transporting polypeptide 1B1 (OATP1B1). Phase 1 studies in healthy participants were subsequently conducted to assess the clinical significance of transporter-mediated DDI potentials of bemnifosbuvir as a precipitant using digoxin and rosuvastatin as P-gp and BCRP/OATP1B1 index substrates, respectively. A single dose of 0.25 mg digoxin or 10 mg rosuvastatin was administered alone and with 1100 mg bemnifosbuvir, either simultaneously or staggered. Simultaneous administration of a single dose of 1100 mg bemnifosbuvir increased total plasma exposure of both drugs by less than 20%, and transiently increased the peak plasma exposure of digoxin and rosuvastatin by 78% and 40%, respectively. Staggered dosing reduced the magnitude of changes in peak exposure to digoxin and rosuvastatin. No serious adverse events or drug discontinuations were observed. Dose adjustments are therefore unlikely for drugs that are substrates of P-gp or BCRP/OAT1B1 when coadministered with bemnifosbuvir, and staggered dosing may further reduce any DDI risk.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182430","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

Dose Optimization of BIIB107, an Anti-Alpha-4 Integrin Monoclonal Antibody, Through Population Pharmacokinetic and Pharmacodynamic Modeling. 抗α -4整合素单克隆抗体BIIB107的剂量优化——基于群体药代动力学和药效学模型

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-27 DOI: 10.1002/jcph.70109

Marie Toukam, Negin Karimian, Eris Bame, Yan Xu

{"title":"Dose Optimization of BIIB107, an Anti-Alpha-4 Integrin Monoclonal Antibody, Through Population Pharmacokinetic and Pharmacodynamic Modeling.","authors":"Marie Toukam, Negin Karimian, Eris Bame, Yan Xu","doi":"10.1002/jcph.70109","DOIUrl":"https://doi.org/10.1002/jcph.70109","url":null,"abstract":"BIIB107 is a recombinant, humanized monoclonal antibody targeting α4 integrin receptors, exhibiting a high binding affinity and strong receptor engagement potential in preclinical models, designed to prevent lymphocyte trafficking in multiple sclerosis (MS). This study aimed to characterize its pharmacokinetics (PK) and pharmacokinetic-pharmacodynamic (PK-PD) relationship using model-based approaches to inform dose optimization. A Phase 1 study (NCT04593121) was conducted in 76 healthy volunteers who received single ascending doses intravenously or subcutaneously (SC), along with multiple ascending doses SC. Population PK and PK-PD models were developed to quantify BIIB107 disposition and its effect on α4 integrin receptor saturation. A sigmoidal Emax model was used to characterize the concentration-effect relationship, and Monte Carlo simulations assessed dosing strategies for sustained α4 integrin engagement. BIIB107 exhibited nonlinear, target-mediated clearance, best described by a two-compartment model with first-order absorption and Michaelis-Menten elimination. Body weight was included in the model using allometric scaling on clearance and volume of distribution-related parameters. In a 70-kg subject, key PK parameters included clearance, 7.28 mL/h; central and peripheral compartment Vd, 3.01 and 1.18 L; terminal half-life 19.3 days; and SC bioavailability 73.8%. PK-PD analysis demonstrated dose-dependent α4 integrin saturation, with an EC50 of 0.376 µg/mL. Simulations showed that 450 mg SC every 8 weeks maintained sustained α4 integrin saturation ≥70%, the therapeutic threshold for efficacy, supporting this regimen for investigation in MS patients. These findings emphasize the value of model-informed drug development in optimizing therapeutic monoclonal antibody doses and support BIIB107's further clinical advancement.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182449","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

Exogenous Melatonin and Sleep Quality: A Scoping Review of Systematic Reviews. 外源性褪黑素与睡眠质量：系统综述的范围综述。

IF 2.3 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-09-27 DOI: 10.1002/jcph.70115

Samyuktha Iyer, Vaneesha Monk, Rebeccah Slater, Luke Baxter

{"title":"Exogenous Melatonin and Sleep Quality: A Scoping Review of Systematic Reviews.","authors":"Samyuktha Iyer, Vaneesha Monk, Rebeccah Slater, Luke Baxter","doi":"10.1002/jcph.70115","DOIUrl":"https://doi.org/10.1002/jcph.70115","url":null,"abstract":"Melatonin is increasingly used to treat sleep disturbances, yet its overall efficacy remains unclear due to variability in existing evidence. This scoping review aimed to synthesize systematic reviews with meta-analyses assessing the effects of exogenously administered melatonin on sleep quality in humans. Seven databases were searched from inception to July 9, 2025. Eligible studies were systematic reviews containing at least one meta-analysis evaluating melatonin's effects on any domain of sleep quality compared to any comparator. Fifty-seven systematic reviews were included, comprising 227 meta-analyses. Overlap in primary studies was low (corrected covered area = 2.5%), suggesting that reviews drew on largely distinct evidence bases. Methodological quality was variable: only 8.8% of reviews met all seven predefined criteria for rigor, including protocol pre-registration, dual screening, and bias assessments. Vote counting based on the direction of effect was used to summarize efficacy. Of the 215 meta-analyses comparing melatonin to an inactive comparator, 80.9% favored melatonin, 7.9% favored the comparator, and 11.2% reported unclear results. Sleep quality was assessed using heterogeneous definitions and tools, with few reviews evaluating overall sleep quality directly. Adverse events were commonly reported and generally mild, with headaches, gastrointestinal problems, and dizziness most frequently observed. However, inconsistent terminology and reporting limited synthesis. Despite heterogeneity in review methods and outcome definitions, the direction of evidence consistently favored melatonin over placebo. These findings support the feasibility of a future quantitative umbrella review to estimate pooled effects and guide clinical practice.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182424","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