The Journal of Clinical Pharmacology最新文献

{"title":"Efanesoctocog Alfa Population Pharmacokinetics and Repeated Time-To-Event Analysis of Bleeds in Adults, Adolescents, and Children with Severe Hemophilia A","authors":"Nancy Wong PhD,&nbsp;Pratik Bhagunde PhD,&nbsp;Joakim Nyberg PhD,&nbsp;Suresh Katragadda PhD,&nbsp;Marek Demissie MD, PhD,&nbsp;Annemieke Willemze MD,&nbsp;Craig Benson MD,&nbsp;Sreeraj Macha PhD","doi":"10.1002/jcph.70008","DOIUrl":"10.1002/jcph.70008","url":null,"abstract":"<p>Efanesoctocog alfa is a first-in-class high-sustained factor VIII (HSF) replacement therapy for treatment of hemophilia A. This article presents population pharmacokinetics (PopPK) of efanesoctocog alfa and repeated time-to-event (RTTE) analysis of bleeding episodes in adults/adolescents (≥12 years of age) and children (&lt;12 years). The final PopPK dataset contained pooled data from 277 patients (4405 post-dose factor VIII [FVIII] activity records) from two Phase 1/2a studies (NCT03205163; EudraCT 2018-001535-51), and three Phase 3 studies, XTEND-1 (NCT04161495), XTEND-Kids (NCT04759131), and XTEND-ed (NCT04644575). The PopPK model developed was a linear one-compartment model including body weight effect on clearance and volume of central compartment; Asian race was identified as a statistically significant covariate on clearance. The final PopPK model adequately described the FVIII activity–time profiles in adults, adolescents, and children with once-weekly (QW) efanesoctocog alfa 50 IU/kg, consistent with experience in XTEND-1 and XTEND-Kids. Bleeding episodes in participants in XTEND-1 and XTEND-Kids were characterized by an RTTE model with a Weibull base hazard and effect of FVIII activity modeled by a power effect. The RTTE model showed the probability of being bleed-free in 1 year with efanesoctocog alfa 50 IU/kg QW regimen was &gt;70% across all age groups, consistent with the observed clinical outcomes in the Phase 3 trials of highly effective protection from bleeding episodes in patients with severe hemophilia A, which validates the model's prediction of the long-term bleed hazard.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 7","pages":"860-872"},"PeriodicalIF":0.0,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694243","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":"Pharmacokinetics and Safety of Fenofibrate in Participants with Mild Hepatic Impairment or with Advanced Fibrosis due to Metabolic-Associated Fatty Liver Disease","authors":"Islam R. Younis PhD, FCP,&nbsp;Elijah J. Weber PhD,&nbsp;Cara Nelson PhD,&nbsp;Ann R. Qin PhD,&nbsp;Timothy R. Watkins MD, MSc,&nbsp;Ahmed A. Othman PhD, FCP","doi":"10.1002/jcph.70005","DOIUrl":"10.1002/jcph.70005","url":null,"abstract":"<p>Fenofibrate is contraindicated in patients with advanced hepatic fibrosis due to limited clinical data. We evaluated the pharmacokinetics and safety of fenofibrate in participants with mild hepatic impairment (phase 1 study) or advanced fibrosis due to metabolic-associated fatty liver disease (MAFLD; phase 2a study). In the phase 1 study, participants with mild hepatic impairment and healthy matched controls (each n = 10) received a single, oral dose of fenofibrate 48 mg. In the phase 2a study, participants with hypertriglyceridemia and advanced fibrosis due to MAFLD were randomly assigned (1:1) fenofibrate 48 mg (n = 15) or fenofibrate 145 mg (n = 16) combined with firsocostat 20 mg, taken orally once daily for 24 weeks. Pharmacokinetics and safety were assessed in both studies. In the phase 1 study, the AUC_inf of fenofibric acid was 25% higher in participants with mild hepatic impairment than in healthy matched participants. In the phase 2a study, the AUC_ss,0-24 of fenofibric acid (fenofibrate 48 mg dose) in participants with F3 fibrosis and F4 cirrhosis was approximately 60% and 80%, respectively, higher than the AUC_inf in healthy participants in the phase 1 study, and was 20% higher in participants with F4 cirrhosis than in participants with F3 fibrosis. In both studies, most adverse events and laboratory abnormalities were grade 1-2. In the phase 2a study, three participants had grade 3 hypertriglyceridemia. Fenofibrate was well tolerated, and modest differences were observed in fenofibric acid exposure in participants with mild hepatic impairment or advanced fibrosis due to MAFLD.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 7","pages":"850-859"},"PeriodicalIF":0.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574419","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":"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":"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}

{"title":"Mathematical Albumin Function for Neonates Undergoing Therapeutic Hypothermia in Comparison with Control Neonates","authors":"Zoë Vander Elst MD,&nbsp;Thibault Stultjens MD,&nbsp;Pieter Annaert PhD,&nbsp;Paul Clarke MD,&nbsp;Isabek Iglesias-Platas PhD,&nbsp;Elisabeth Agathos MD,&nbsp;Gozdem Kaykı MD,&nbsp;Annouschka Laenen PhD,&nbsp;Nadir Yalçın PhD,&nbsp;Anne Smits PhD,&nbsp;Karel Allegaert PhD","doi":"10.1002/jcph.70003","DOIUrl":"10.1002/jcph.70003","url":null,"abstract":"<p>Hypoxic-ischemic encephalopathy (HIE) resulting from perinatal asphyxia presents a substantial risk of mortality and long-term sequelae in neonates. Therapeutic hypothermia (TH) improves both short- and long-term outcomes in near-term/term neonates with moderate to severe HIE. While neonates with perinatal asphyxia and TH often require polypharmacy, the impact of both covariates on pharmacokinetics and pharmacodynamics is only partially described and quantified. In this pooled, multicenter retrospective study, longitudinal trends of human serum albumin (HSA, the major drug binding protein) and total protein (TP) concentrations in near-term/term neonates were described using linear mixed models and compared between cohorts (TH vs control neonates, and moderate vs severe HIE TH cases). A mathematical function for HSA concentrations in neonates with HIE undergoing TH was derived (AlbuCool function). The pooled dataset to estimate these functions contained 330 TH neonates and 425 controls with 1725 and 1415 HSA observations, respectively. The median (interquartile range) HSA concentration was 27.0 (23.0-31.0) g/L for the TH cohort, and 32.1 (28.4-35.7) g/L for the control cohort. Estimated mean HSA concentrations were significantly lower (<i>P</i> &lt; .001) in TH compared to control cases, as well as in severe compared to moderate HIE cases (<i>P</i> &lt; .001) over the first 7 postnatal days. The HSA function for neonates with HIE undergoing TH was: HSA (g/L) = 32.28 − 2.94 * PNA + 0.33 * PNA² (PNA is postnatal age). The integration of this function in pharmacokinetic models holds the promise to improve the predictive performance of these models, and consequently, the pharmacotherapy of HSA-bound drugs in this vulnerable population.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 7","pages":"923-932"},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392096","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}