The Journal of Clinical Pharmacology最新文献

{"title":"Comparing the Efficacy of Various Insulin Types: Pharmacokinetic and Pharmacodynamic Modeling of Glucose Clamp Effects in Healthy Volunteers","authors":"Yi Chien Chang MS,&nbsp;William J. Jusko PhD","doi":"10.1002/jcph.70010","DOIUrl":"10.1002/jcph.70010","url":null,"abstract":"<p>This study compares the pharmacokinetics and efficacy of various subcutaneously (SC) dosed insulin analogs, including rapid-acting, intermediate-acting, long-acting, and regular human insulin, using mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) models. These models were applied to data from euglycemic clamp studies in healthy volunteers, where insulin pharmacokinetics and its effects on glucose utilization were monitored. Data from published studies were digitized and modeled using MONOLIX (Version 2024). The PK model described insulin absorption via sequential first-order processes and linear elimination. The PD effects were captured using a model combination of biophase, indirect, and receptor down-regulation components. While PK parameters—especially absorption rates—varied between insulin types, a common set of nonlinear PD parameters was sought to account for dose-related differences in glucose utilization. The maximum glucose stimulation (<span></span><math>\u0000 <semantics>\u0000 <msub>\u0000 <mi>S</mi>\u0000 <mi>max</mi>\u0000 </msub>\u0000 <annotation>${{{mathrm{S}}}_{{mathrm{max}}}}$</annotation>\u0000 </semantics></math>) was 163, and the insulin concentration for a half-maximal effect (<span></span><math>\u0000 <semantics>\u0000 <mrow>\u0000 <mi>S</mi>\u0000 <msub>\u0000 <mi>C</mi>\u0000 <mn>50</mn>\u0000 </msub>\u0000 </mrow>\u0000 <annotation>${mathrm{S}}{{{mathrm{C}}}_{50}}$</annotation>\u0000 </semantics></math>) were 1156 pmol/L for insulin lispro, regular human insulin, neutral protamine hagedorn (NPH) insulin, and insulin glargine; 674 pmol/L for insulin aspart; and 5335 pmol/L for insulin detemir. Insulin detemir showed similar overt effects as the other insulin types but with smaller clearances and lower potency. This mechanism-based glucose–insulin model demonstrated that most insulin analogs exhibit similar receptor- and transporter-related parameters. The model, with specific PK but unified PD parameters, may enable clinical optimization of insulin therapy by highlighting differences in pharmacokinetics and operating common intrinsic glucose utilization parameters.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 8","pages":"999-1010"},"PeriodicalIF":0.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143469738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ertapenem in the Context of Hypoalbuminemia: Implications for Critically Ill Patients","authors":"Micaela Elene Seazzu PharmD,&nbsp;M. Gabriela Cabanilla PharmD, PhC","doi":"10.1002/jcph.70011","DOIUrl":"10.1002/jcph.70011","url":null,"abstract":"<p>The global rise in extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) has created significant challenges in the management of severe infections, including bacteremia. Ertapenem, a once-daily carbapenem with high protein-binding affinity (85%-95%), is an ideal option for ESBL-E because of its spectrum and dosing convenience. However, hypoalbuminemia, a common condition in critically ill patients that is independently associated with poor outcomes, raises concerns about altered pharmacokinetics, specifically increased free drug fractions, enhanced clearance, and shortened half-life. These pharmacokinetic changes have been hypothesized to lead to suboptimal drug levels and treatment failure, although clinical evidence remains inconsistent. This narrative review examines ertapenem's pharmacokinetic and pharmacodynamic changes in patients with hypoalbuminemia, focusing on its clinical implications. While some studies have reported suboptimal outcomes in critically ill patients, others have demonstrated comparable efficacy to broader spectrum carbapenems when minimum inhibitory concentration values are favorable, and source control is achieved. These findings challenge the concerns raised in the 2024 Infectious Diseases Society of America Gram-negative resistance guidance, which cautions against ertapenem use in patients with hypoalbuminemia. Rather than universally avoiding ertapenem, clinicians should prioritize individualized decision making based on patient-specific factors. Further research is warranted to optimize dosing strategies. However, current data suggest that ertapenem remains a viable and effective option in this high-risk population when used judiciously.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 8","pages":"961-969"},"PeriodicalIF":0.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Fragmented Data to Integrated Drug Development in Asphyxiated Neonates Undergoing Therapeutic Hypothermia","authors":"Karel Allegaert PhD,&nbsp;Pieter Annaert PhD,&nbsp;Anne Smits PhD","doi":"10.1002/jcph.70012","DOIUrl":"10.1002/jcph.70012","url":null,"abstract":"&lt;p&gt;Methylxanthines are very commonly administered to preterm (gestational age [GA] &lt; 37 weeks) neonates in whom they are associated with improved respiratory, renal, and neurodevelopmental outcomes. More recently, these drugs are also considered for several indications in full-term (GA 37-42 weeks) or near-term (GA 34/35-36 weeks) neonates. Suggested mechanisms of the observed beneficial effects relate to respiratory stimulation, as well as anti-inflammatory, diuretic, and renal protective effects, in part by interaction with the adenosine A3 receptor (&lt;i&gt;ADORA3&lt;/i&gt;). Therefore, we read with great interest the recent paper in the journal on caffeine pharmacokinetics in asphyxiated neonates undergoing therapeutic hypothermia following moderate to severe encephalopathy.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; It is our understanding that this paper is part of a planned drug development program to explore the potential add-on value of caffeine on neurological outcomes after perinatal asphyxia.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;This commentary likes to reflect on how to improve the workflow, the feasibility, and ways to reduce the uncertainties of drug development plans (e.g., sampling strategy and dose/exposure relationship). The ultimate goal of such a structured approach is to evolve toward personalized pharmacotherapy (e.g., precision dosing) in this specific population. We already earlier suggested that a subpopulation-specific physiologically based pharmacokinetic (PBPK) model is probably such a strategy.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;PBPK modeling and simulation imply that we collect data on both drug-specific characteristics (&lt;i&gt;what is known about the drug?)&lt;/i&gt;, as well as on population-relevant physiology characteristics (&lt;i&gt;what is known about the targeted population relevant to the planned PK study?)&lt;/i&gt; (Figure 1). Preclinical findings (animal research, in vitro data) can further inform such efforts. This approach might also have informed the caffeine research team on how to conduct their trial, for example, sampling strategy or targeted exposure.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Related to drug-specific aspects, this covers, for example, physicochemical characteristics of the drug or reported absorption, distribution, metabolism, and excretion (ADME) properties in other populations, including the formation of metabolites. Related to the targeted population (in this case, asphyxiated neonates undergoing therapeutic hypothermia), this includes aspects like weight or gestational age range, enzyme ontogeny, cardiac output and organ-specific blood flow, glomerular filtration rate (GFR), or specific (patho)physiological characteristics.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Because of the notorious time-dependent physiology of this subpopulation, such data are at best longitudinal over postnatal age, and weighted to similar data in non-asphyxiated cohorts, as very recently reported for albumin values in this journal.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The elimination hal","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 7","pages":"944-947"},"PeriodicalIF":0.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Impact of Augmented Renal Clearance on the Pharmacokinetics of Levetiracetam in Critically Ill Patients: A Literature Review","authors":"Maged Kharouba BSc (Pharm),&nbsp;Asma Aboelezz MSc,&nbsp;Janice Y. Kung MLIS,&nbsp;Sherif Hanafy Mahmoud PhD","doi":"10.1002/jcph.70007","DOIUrl":"10.1002/jcph.70007","url":null,"abstract":"<p>Levetiracetam is an antiseizure medication (ASM) that has several advantages over other ASMs, such as dose-proportional pharmacokinetics, high bioavailability, and minimal drug interactions. The drug is primarily eliminated through the kidneys. Therefore, dose adjustments are necessary in patients with renal impairment or patients experiencing augmented renal clearance (ARC) to maintain optimal efficacy and safety. The objective of this review was to explore the existing literature on the influence of ARC on the pharmacokinetics of levetiracetam in critically ill patients. Database searched included MEDLINE, Embase, Scopus, Cochrane Library, and CINAHL. Thirteen articles were included. The prevalence of ARC ranged from 30% to 90%. All studies demonstrated the inadequacy of the levetiracetam starting dose of 500 mg twice daily (BID) in critically ill patients. Studies consistently reported altered pharmacokinetics of levetiracetam in patients with ARC, showing an elevated clearance that can reach up to 6.5L/h (∼3.8 L/h in healthy individuals). Additionally, patients with ARC had a lower area under the concentration-time curve, shorter half-life, and lower trough concentrations than those without ARC. Dosing simulations indicated that the use of at least 1500 mg BID is recommended for ARC patients to achieve similar exposures to those with no ARC on the 1000 mg BID starting dose. In conclusion, ARC significantly enhances the renal elimination of levetiracetam, elevating the risk of sub-therapeutic drug levels and treatment failure. An initial dosage regimen of 1500 mg BID would be recommended for patients exhibiting ARC. Therefore, careful monitoring of creatinine clearance and dosing optimization for patients experiencing ARC is essential.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 7","pages":"815-834"},"PeriodicalIF":0.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics of Fruquintinib, a Selective Oral Inhibitor of VEGFR -1, -2, and -3, in Patients with Refractory Metastatic Colorectal Cancer","authors":"Xiaofei Zhou PhD,&nbsp;Xiaoyan Yang PhD,&nbsp;Boris Grinshpun PhD,&nbsp;Adekemi Taylor PhD,&nbsp;Laura Strong PhD,&nbsp;Arvind Dasari MD,&nbsp;Andrea Wang-Gillam MD, PhD,&nbsp;Jin Li MD,&nbsp;Rui-Hua Xu MD,&nbsp;Neeraj Gupta PhD, FCP,&nbsp;Caly Chien PhD","doi":"10.1002/jcph.70001","DOIUrl":"10.1002/jcph.70001","url":null,"abstract":"<p>Fruquintinib is a selective, oral tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors 1, 2, and 3, which is approved for patients with previously treated metastatic colorectal cancer regardless of biomarker status. This population pharmacokinetic (PK) analysis characterized sources of interpatient variability on the PK of fruquintinib and its major metabolite M11 using data from 557 subjects who received fruquintinib in five phase I/Ib studies and the FRESCO-2 phase III study. The integrated model was a one-compartment model with first-order absorption, lag time in absorption, and linear elimination for fruquintinib and a one-compartment model with linear elimination for M11. The half-life of fruquintinib and M11 were estimated to be 43.2 and 54 h, respectively. Fruquintinib PK demonstrated dose proportionality. Fruquintinib oral clearance and apparent volume of distribution (V/F) increased with increasing body weight. Fruquintinib absorption rate constant was 60.7% lower with concurrent use of proton-pump inhibitors (PPIs), and fruquintinib V/F was 9.08% lower in healthy subjects versus patients with cancer. Magnitudes of the covariate effects of body weight, concurrent use of PPIs, and health status on fruquintinib exposures were estimated to be &lt;20%, which is not considered clinically meaningful. Age (18.0-82.0 years), sex, race (Asian, Black, and White), ethnicity (Hispanic vs non-Hispanic), Eastern Cooperative Oncology Group performance status score, tumor type, mild or moderate renal impairment, and mild hepatic impairment had no clinically meaningful impact on fruquintinib or M11 PK. This analysis supports the same fruquintinib starting dosage, without need for adjustments, for these patient-specific factors.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 7","pages":"873-884"},"PeriodicalIF":0.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effects of the Early and Late Phases of Septic Shock on the Population Pharmacokinetics of Vancomycin","authors":"Tanisa Lexnoi PharmD,&nbsp;Apinya Boonpeng PhD,&nbsp;Wichai Santimaleeworagun PhD,&nbsp;Kessarin Chaisiri MS,&nbsp;Jutamas Dechsanga MD,&nbsp;Veerapong Vattanavanit MD,&nbsp;Chutchawan Ungthammakhun MD,&nbsp;Sirima Sitaruno PharmD","doi":"10.1002/jcph.70009","DOIUrl":"10.1002/jcph.70009","url":null,"abstract":"<p>Pathophysiologic changes in the early and late phases of septic shock affect the pharmacokinetic (PK) parameters, varying dose adjustments may be necessary. This study aimed to create the PK models of vancomycin in the early and late phases of septic shock and to describe the association between the area under the curve from 0 to 24 h (AUC_0-24) and acute kidney injury (AKI). The data from patients with septic shock receiving vancomycin was collected either prospectively or retrospectively. A nonlinear mixed-effects modeling approach was used to develop the PK models. A total of 208 septic shock patients were enrolled and classified into the early (n = 96) and the late phase (n = 112). A two-compartment PK model is the best base model for both phases of septic shock. The model that best predicted the clearance (CL) of both phases was the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, which was not indexed to body surface area (BSA). Albumin (ALB) was a covariate associated with vancomycin CL only in the late phase. The typical values of CL and volume of distribution (V_d) in the early phase were 1.71 L/h and 68.94 L. In the late phase, CL was 1.65 L/h, and V_d was 66.36 L. The AKI was observed in patients with a high simulated AUC_0-24. The population PK model of vancomycin in the early and late phases of septic shock has been established. The CKD-EPI not indexed to BSA predicts vancomycin CL in both phases. ALB was associated with CL in the late phase.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 8","pages":"970-979"},"PeriodicalIF":0.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JCP Annual Reviewer List","authors":"","doi":"10.1002/jcph.70006","DOIUrl":"https://doi.org/10.1002/jcph.70006","url":null,"abstract":"&lt;p&gt;The Editors of &lt;i&gt;The Journal of Clinical Pharmacology&lt;/i&gt; would like to acknowledge and thank our peer reviewers for their contribution to the journal. Below is a list of those individuals who reviewed for &lt;i&gt;JCP&lt;/i&gt; in 2024.&lt;/p&gt;&lt;p&gt;Claude Abdallah&lt;/p&gt;&lt;p&gt;Mariam Ahmed&lt;/p&gt;&lt;p&gt;Karel Allegaert&lt;/p&gt;&lt;p&gt;Barbara Ameer&lt;/p&gt;&lt;p&gt;Elham Amini&lt;/p&gt;&lt;p&gt;Guohua An&lt;/p&gt;&lt;p&gt;Marion Anliker-Ort&lt;/p&gt;&lt;p&gt;Glen Apseloff&lt;/p&gt;&lt;p&gt;Vikram Arya&lt;/p&gt;&lt;p&gt;Amal Ayyoub&lt;/p&gt;&lt;p&gt;April Barbour&lt;/p&gt;&lt;p&gt;Luke Baxter&lt;/p&gt;&lt;p&gt;Dallas Bednarczyk&lt;/p&gt;&lt;p&gt;Charles Berde&lt;/p&gt;&lt;p&gt;Simon Berger&lt;/p&gt;&lt;p&gt;Chandrali Bhattacharya&lt;/p&gt;&lt;p&gt;Robert Bies&lt;/p&gt;&lt;p&gt;Xavier Boulenc&lt;/p&gt;&lt;p&gt;Dominic Bräm&lt;/p&gt;&lt;p&gt;Dion Brocks&lt;/p&gt;&lt;p&gt;Kristina Brooks&lt;/p&gt;&lt;p&gt;Gilbert Burckart&lt;/p&gt;&lt;p&gt;David Burger&lt;/p&gt;&lt;p&gt;Jan Steven Burgerhart&lt;/p&gt;&lt;p&gt;James Burris&lt;/p&gt;&lt;p&gt;Elisa Calvier&lt;/p&gt;&lt;p&gt;Yanguang Cao&lt;/p&gt;&lt;p&gt;Bruce Carleton&lt;/p&gt;&lt;p&gt;Francisco Cezar&lt;/p&gt;&lt;p&gt;Ayyappa Chaturvedula&lt;/p&gt;&lt;p&gt;Bing Chen&lt;/p&gt;&lt;p&gt;Cuiping Chen&lt;/p&gt;&lt;p&gt;Qiaoxi Chen&lt;/p&gt;&lt;p&gt;Hee-Jae Choi&lt;/p&gt;&lt;p&gt;Imti Choonara&lt;/p&gt;&lt;p&gt;Sheryl Coppola&lt;/p&gt;&lt;p&gt;Michael Court&lt;/p&gt;&lt;p&gt;Tim Cressey&lt;/p&gt;&lt;p&gt;André Dallmann&lt;/p&gt;&lt;p&gt;Borje Darpo&lt;/p&gt;&lt;p&gt;Sjoerd de Hoogd&lt;/p&gt;&lt;p&gt;Natalia de Moraes&lt;/p&gt;&lt;p&gt;Saskia de Wildt&lt;/p&gt;&lt;p&gt;Jasper Dingemanse&lt;/p&gt;&lt;p&gt;Stefanie Drescher&lt;/p&gt;&lt;p&gt;Andrea Edginton&lt;/p&gt;&lt;p&gt;Taher Entezari-Maleki&lt;/p&gt;&lt;p&gt;Thomas Erb&lt;/p&gt;&lt;p&gt;Kerry Estes&lt;/p&gt;&lt;p&gt;Ene Ette&lt;/p&gt;&lt;p&gt;Federica Ferrari&lt;/p&gt;&lt;p&gt;William Figg&lt;/p&gt;&lt;p&gt;Michael Fossler&lt;/p&gt;&lt;p&gt;Yoko Franchetti&lt;/p&gt;&lt;p&gt;Lan Gao&lt;/p&gt;&lt;p&gt;Francis Gengo&lt;/p&gt;&lt;p&gt;Paul Glue&lt;/p&gt;&lt;p&gt;Klervi Golhen&lt;/p&gt;&lt;p&gt;Mathangi Gopalakrishnan&lt;/p&gt;&lt;p&gt;Verena Gotta&lt;/p&gt;&lt;p&gt;Navin Goyal&lt;/p&gt;&lt;p&gt;Howard Greenberg&lt;/p&gt;&lt;p&gt;Yue Guo&lt;/p&gt;&lt;p&gt;Manish Gupta&lt;/p&gt;&lt;p&gt;Neeraj Gupta&lt;/p&gt;&lt;p&gt;Arthur Harralson&lt;/p&gt;&lt;p&gt;Hazem Hassan&lt;/p&gt;&lt;p&gt;Eric Helmer&lt;/p&gt;&lt;p&gt;Guenther Hochhaus&lt;/p&gt;&lt;p&gt;Christoph Hornik&lt;/p&gt;&lt;p&gt;Marissa Anne Horrigan&lt;/p&gt;&lt;p&gt;Chuanpu Hu&lt;/p&gt;&lt;p&gt;Angela Jeong&lt;/p&gt;&lt;p&gt;Kunal Jhunjhunwala&lt;/p&gt;&lt;p&gt;Yu Jiang&lt;/p&gt;&lt;p&gt;Zheng Jiao&lt;/p&gt;&lt;p&gt;William Jusko&lt;/p&gt;&lt;p&gt;Shamir Kalaria&lt;/p&gt;&lt;p&gt;Tobias Kanacher&lt;/p&gt;&lt;p&gt;Gary Kaplan&lt;/p&gt;&lt;p&gt;Michael Kays&lt;/p&gt;&lt;p&gt;Gregory Kearns&lt;/p&gt;&lt;p&gt;Tony Kiang&lt;/p&gt;&lt;p&gt;Myong-Jin Kim&lt;/p&gt;&lt;p&gt;Mark Kirstein&lt;/p&gt;&lt;p&gt;Gilbert Koch&lt;/p&gt;&lt;p&gt;Joan Korth-Bradley&lt;/p&gt;&lt;p&gt;Elke Krekels&lt;/p&gt;&lt;p&gt;Rajesh Krishna&lt;/p&gt;&lt;p&gt;Parag Kumar&lt;/p&gt;&lt;p&gt;K. E. Kvitne&lt;/p&gt;&lt;p&gt;Mayur Ladumor&lt;/p&gt;&lt;p&gt;Brooke Langevin&lt;/p&gt;&lt;p&gt;Lucy Lee&lt;/p&gt;&lt;p&gt;David Lehmann&lt;/p&gt;&lt;p&gt;Xiaonan Li&lt;/p&gt;&lt;p&gt;Yali Liang&lt;/p&gt;&lt;p&gt;Yi Ting Lien&lt;/p&gt;&lt;p&gt;Shufang Liu&lt;/p&gt;&lt;p&gt;Xiaomei Liu&lt;/p&gt;&lt;p&gt;Pradeep Lukka&lt;/p&gt;&lt;p&gt;Donald Mager&lt;/p&gt;&lt;p&gt;Kelly Mahar&lt;/p&gt;&lt;p&gt;Paul Malik&lt;/p&gt;&lt;p&gt;Ron Mathot&lt;/p&gt;&lt;p&gt;Ilan Matok&lt;/p&gt;&lt;p&gt;Anna M. Mc Laughlin&lt;/p&gt;&lt;p&gt;Jaydeep Mehta&lt;/p&gt;&lt;p&gt;Bernd Meibohm&lt;/p&gt;&lt;p&gt;Peter Mesenbrink&lt;/p&gt;&lt;p&gt;Gerd Mikus&lt;/p&gt;&lt;p&gt;Jeremiah Momper&lt;/p&gt;&lt;p&gt;Jatinder Mukker&lt;/p&gt;&lt;p&gt;Anne Nafziger&lt;/p&gt;&lt;p&gt;James Nguyen&lt;/p&gt;&lt;p&gt;Toan Duc Nguyen&lt;/p&gt;&lt;p&gt;Jin Niu&lt;/p&gt;&lt;p&gt;Maria Noftz&lt;/p&gt;&lt;p&gt;Ken Ogasawara&lt;/p&gt;&lt;p&gt;Kayode Ogungbenro&lt;/p&gt;&lt;p&gt;Charles Oo&lt;/p&gt;&lt;p&gt;Manjunath Pai&lt;/p&gt;&lt;p&gt;Keyur Parmar&lt;/p&gt;&lt;p&gt;Richard Parrish&lt;/p&gt;&lt;p&gt;Cody Peer&lt;/p&gt;&lt;p&gt;Scott Penzak&lt;/p&gt;&lt;p&gt;George Perentesis&lt;/p&gt;&lt;p&gt;Juan Jose Perez Ruixo&lt;/p&gt;&lt;p&gt;Sheila Annie Peters&lt;/p&gt;&lt;p&gt;Elimika Pfuma Fletcher&lt;/p&gt;&lt;p&gt;Natella Rakhmanina&lt;/p&gt;&lt;p&gt;Arun Ram&lt;/p&gt;&lt;p&gt;Michael Reed&lt;/p&gt;&lt;p&gt;Michael Rieder&lt;/p&gt;&lt;p&gt;Karen Rowland-Yeo&lt;/p&gt;&lt;p&gt;Ana Ruiz-Garcia&lt;/p&gt;&lt;p&gt;Ma","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"533-534"},"PeriodicalIF":0.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics of Caffeine in Infants with Hypoxic-Ischemic Encephalopathy: A Phase I, Dose-Escalating Trial","authors":"Elizabeth J Thompson MD,&nbsp;Daniel Gonzalez PharmD, PhD,&nbsp;Julie Dumond PharmD, MS,&nbsp;Christoph P Hornik MD, PhD, MPH,&nbsp;Alison Kilborn BS,&nbsp;Matthew M Laughon MD, MPH,&nbsp;Wesley M Jackson MD, MPH","doi":"10.1002/jcph.70004","DOIUrl":"10.1002/jcph.70004","url":null,"abstract":"<p>The mainstay of treatment for infants with hypoxic-ischemic encephalopathy (HIE) is cooling. Caffeine may be an important adjunct to cooling and provide neuroprotection via its anti-inflammatory and anti-oxidative properties. This study aimed to characterize caffeine pharmacokinetics in term infants with HIE receiving cooling.</p><p>In this phase 1, dose-escalating study, enrolled infants received IV caffeine 20 mg/kg followed by up to two daily doses of 5 or 10 mg/kg. A population pharmacokinetic analysis was performed using NONMEM (v7.5). The effects of clinical covariates, including cooling, on pharmacokinetic parameters were evaluated. Dosing simulations were performed to evaluate the percentage of plasma exposures in the reference range (15-25 mg/L).</p><p>Seventeen infants were included in model development. A one-compartment model best fit the data. Population clearance was 0.445 L/h/70 kg and volume of distribution was 87.1 L/70 kg. Current dosing regimens (20 mg/kg followed by 5 mg/kg) resulted in 89.5% of infants having at least one simulated exposure below the reference range across the dosing interval. Dosing regimens of 30 mg/kg followed by 5 or 10 mg/kg were predicted to result in more than half of infants achieving simulated exposures in the reference range, with ≤2% of infants having simulated exposures in the toxic range (&gt;46 mg/L).</p><p>Term infants with HIE had similar weight-normalized clearance but higher weight-normalized volume of distribution compared to prior studies in preterm infants without HIE or cooling. While exposure targets for neuroprotection in HIE are unknown, this phase 1 study suggests alternate dosing strategies should be considered in future studies.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 7","pages":"933-943"},"PeriodicalIF":0.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating First-in-Human and Early-Phase Patient Studies: Study Designs, Risk Mitigation, and Population Selection Challenges","authors":"Jocelyn Courville PhD,&nbsp;Amanda Barber BS,&nbsp;Aberra Fura PhD","doi":"10.1002/jcph.70002","DOIUrl":"10.1002/jcph.70002","url":null,"abstract":"<p>First–in-human (FIH) and early-phase clinical studies have increasingly become an integral part of the entire clinical development process, applying integrated protocols and robust risk mitigation strategies to enhance participant safety and development efficiency. This manuscript focuses on the diverse study designs employed in FIH studies, strategies for effective risk mitigation, suitable study population selection, and the methodologies and considerations unique to early-phase patient trials. FIH studies typically include single ascending dose (SAD) and multiple ascending dose (MAD) cohorts that may be conducted in healthy volunteers (HVs) or with relevant patient populations. An analysis of 193 compounds approved by the FDA's Center for Drug Evaluation and Research between 2020 and 2023 revealed that 47.7% (92 out of 193) conducted FIH or initial SAD/MAD studies in healthy volunteers, while 39.4% (76 out of 193) initiated their FIH studies in the relevant patient population. The status for 12.9% (25 out of 193) was unknown. Among the programs that did not involve healthy volunteers for FIH or initial SAD/MAD studies, 65.8% (50 out of 76) were developed for oncology indications, whereas the remaining 34.2% (26 out of 76) were involved in therapeutic areas such as rare disease, genetic disorders, and ophthalmology. This manuscript highlights the importance of tailoring scientific and operational approaches to specific molecules, indications, and patient relevance. It provides tools, strategies, and a mind map to effectively navigate challenges during this phase of the development.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 7","pages":"835-849"},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indication-Specific Dosing and Dose-Evaluation Strategies in New Indications for Non-Oncology Monoclonal Antibodies","authors":"Sherouk M. Tawfik MS,&nbsp;Fei Tang PharmD, PhD","doi":"10.1002/jcph.70000","DOIUrl":"10.1002/jcph.70000","url":null,"abstract":"<p>Compared to traditional small molecule drugs, monoclonal antibodies (mAbs) often display more complex pharmacokinetic (PK) and pharmacodynamic (PD) properties that may be impacted by disease-specific factors. For mAbs in non-oncology indications, where the same drug might be used for conditions involving different organ systems and/or having different degrees of severity, the need for indication-specific dosing and/or tailored dose evaluation strategies is more evident. However, a comprehensive analysis on this topic has not been conducted for approved non-oncology therapies. In this work, we extracted literature information for non-oncology mAbs approved in the past 20 years to provide a comprehensive exploration of indication-specific dosing and dose evaluation strategies in the new indications. Our analysis included 21 mAbs with 50 supplemental approvals for new indications. Indication-specific dosing was prevalent, with 15 out of 21 mAbs having different recommended dosing regimens across two or more indications. The majority of the new indications were supported by Phase 2 dose-ranging studies and/or Phase 3 studies that evaluated more than one dosing regimen. Importantly, our analysis uncovered a relationship between indication-specific dosing, dose evaluation strategies, and organ system classification of the original versus the new indication. We delved into dose justification supporting the new indications, including the types of data and modeling approaches used or considered. Through case studies, we highlighted factors that may influence dose selection in new indications, such as target expression levels, disease severity, and benefit–risk profile. Lastly, we made practical recommendations regarding dose optimization approaches in clinical drug development across multiple indications.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 7","pages":"895-908"},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}