The Journal of Clinical Pharmacology最新文献

{"title":"The Pharmacokinetics and Relative Bioavailability of a Mini-Tablet of Mercaptopurine, a Novel Formulation for Use in Children with Acute Lymphoblastic Leukemia","authors":"Zhi Chen MS,&nbsp;Yuan-Yuan Zheng MS,&nbsp;Qing-Liang Liu MS,&nbsp;Pan-Pan Ye PhD,&nbsp;Xin-Mei Yang PhD,&nbsp;Lin-Lin Song MS,&nbsp;Ke-Guang Chen PhD,&nbsp;Fu-Rong Zhao MS,&nbsp;Jin-Yi Shi MS,&nbsp;Ye-Hui Zhang MS,&nbsp;Hai-Yan Zhou MS,&nbsp;John van den Anker PhD,&nbsp;Yan Yang MS,&nbsp;Qian Zhao PhD,&nbsp;Qian Li MS,&nbsp;Wen-Chao Lu MS,&nbsp;Yue Zhou PhD,&nbsp;Wei Zhao PhD, PharmD","doi":"10.1002/jcph.70178","DOIUrl":"10.1002/jcph.70178","url":null,"abstract":"<p>A novel 5 mg mini-tablet formulation of mercaptopurine (6-MP) was developed to provide flexible and accurate doses to treat children with acute lymphoblastic leukemia. We conducted two open-label, randomized, single-dose, four-period, two-sequence, full-replicate, crossover trials to characterize the pharmacokinetics and relative bioavailability of the novel 6-MP mini-tablet (N) compared to the reference 6-MP tablet (R) under both fasted and fed conditions. The 6-MP plasma concentrations were measured using ultra performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS). The C_max, AUC_0–t, and AUC_0–inf were used to evaluate the relative bioavailability. The results showed that the 6-MP mini-tablet was bioequivalent to the reference formulation under fasting condition. Under the fasted condition, the geometric least-squares mean ratios (GLSMR) (90% CI) of C_max, AUC_0–t, and AUC_0–inf of N over R were 91.71% (81.31%–103.44%), 97.53% (92.57%–102.76%), and 97.91% (93.17%–102.90%), respectively. The mean CL/F (238.4 vs 219.3 L/h), the mean V_d/F (523.4 vs 451.8 L), the median T_max (1.50 vs 1.25 h), and the mean t_1/2 (1.55 vs 1.44 h) of N and R showed similarity. Under fed condition, the GLSMR (90% CI) of C_max, AUC_0–t, and AUC_0–inf of N over R were 68.16% (59.62%–77.93%), 86.22% (81.37%–91.37%), and 86.59% (81.88%–91.57%), respectively. Furthermore, a high-fat diet increased both CL/F and V_d/F of 6-MP and decreased exposure of 6-MP, with all changes exceeding two-fold. Both products exhibited a favorable safety profile without any SAE being observed. These results supported the marketing of 6-MP mini-tablets.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610409","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":"Beyond Impossibility: Reimagining Clinical Evidence for Children with Ultra-Rare Diseases","authors":"Rajesh Krishna PhD","doi":"10.1002/jcph.70183","DOIUrl":"10.1002/jcph.70183","url":null,"abstract":"&lt;p&gt;Ultra-rare diseases are those conditions with a prevalence of fewer than 1 per 50,000 individuals. This threshold is commonly used in European policy discussions and health technology assessment contexts to distinguish ultra-rare conditions from broader rare disease categories (e.g., fewer than five per 10,000 in the European Union, or fewer than 200,000 affected individuals in the United States). While definitions may vary slightly across jurisdictions, the defining feature of ultra-rare diseases is the extremely small patient population, often numbering in the dozens or low hundreds nationally, and sometimes fewer than 1000 patients worldwide. There are many examples of such low-incidence pediatric ultra-rare diseases, including but not limited to neuronal ceroid lipofuscinosis type 2 disease, a rapidly progressive neurodegenerative disorder of childhood; aromatic L-amino acid decarboxylase deficiency, a severe neurotransmitter synthesis disorder; and fibrodysplasia ossificans progressiva, an ultra-rare condition characterized by progressive heterotopic ossification. Each of these conditions has a prevalence well below the 1 per 50,000 threshold and exemplifies the clinical severity, early onset, and profound unmet need that typify ultra-rare pediatric disorders.&lt;/p&gt;&lt;p&gt;Pediatric ultra-rare diseases are a persistent challenge to clinical research, exposing inherent limitations in conventional trial design and data analysis strategies. Traditional randomized controlled trials, which rely on large sample sizes and statistical power derived from group comparisons, are ill-suited to generate actionable evidence in these contexts. Investigators frequently resort to open-label case series, historical controls, or approaches that compromise interpretability and introduce bias. The result is a persistent evidence gap that delays therapeutic advances and leaves families and clinicians without robust guidance.&lt;/p&gt;&lt;p&gt;Adoption of adaptive methodologies and individualized inference frameworks that can extract maximal value from limited data remains poor. Standard statistical paradigms emphasize population averages, obscuring meaningful within-subject responses that could signal treatment efficacy. Moreover, global regulatory uncertainty and inconsistent analytic standards for single-patient or small-cohort studies further hinder progress. To better understand these gaps, a conceptual case is made to introduce N-of-1 trial designs as a complement to the standard randomized controlled clinical trial designs.&lt;/p&gt;&lt;p&gt;Pivotal trials in rare diseases face a structural tension between methodological rigor and feasibility. Extremely small, geographically dispersed patient populations; phenotypic heterogeneity; ethical concerns about prolonged placebo exposure; and urgent unmet need all challenge conventional evidentiary standards. Within this context, the comparative value of standard randomized controlled trials (RCTs) and N-of-1 designs for conclusively detectin","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70183","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610411","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":"Learnings from Approved Antibody-Drug Conjugates: Clinical Pharmacology Perspectives","authors":"Bhargavi Thalluri MS,&nbsp;Aarti Sawant PhD,&nbsp;Pavan Vajjah PhD,&nbsp;Karthick Vishwanathan PhD,&nbsp;Shringi Sharma PhD","doi":"10.1002/jcph.70166","DOIUrl":"10.1002/jcph.70166","url":null,"abstract":"<p>Over the past decade, antibody-drug conjugates (ADCs) have emerged as promising anti-cancer therapeutics, with twelve ADCs approved by the FDA. This review evaluates trends in these ADCs, stratified by payloads on doses studied from first-in-human (FIH) trials through approval and post-marketing. It summarizes trends in pharmacokinetics (PK), drug–drug interactions (DDI), exposure-response analysis, immunogenicity, and organ impairment. Additionally, it provides perspectives on potential postmarketing requirements associated with clinical pharmacology attributes, and how this knowledge could inform efficient early clinical development of newer ADCs. Except for sacituzumab govitecan, which had a starting dose of 8 mg/kg, starting doses of ADCs ranged from 0.0067 to 0.8 mg/kg. All ADCs have been administered intravenously. Dose escalation generally progressed over four to eight distinct levels, with increments of 20% to 233% at the first three levels. The maximum tolerated dose was achieved by the fourth to seventh dose level in most cases. For 5/12 ADCs, the recommended phase 2 dose and the phase 3 dose were the same as the MTD. Approved doses ranged from 1.25-fold to 40-fold higher than the FIH starting dose levels. Generally, ADCs exhibited dose-proportional PK within the tested dose range. Exposure-response relationships have been reported for ADC/total antibody for efficacy and ADC/total antibody/payload exposures for safety. DDI potential has been reported for payloads associated with auristatins, maytansinoids, and camptothecin: SN38. At approved doses, immunogenicity assessments indicated low incidence of anti-drug antibodies. Organ impairment studies suggest no significant risk in patients with moderate hepatic or renal impairment</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147575987","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":"Understanding Atomoxetine Exposure Variability in Children and Adolescents With ADHD Through Population Pharmacokinetics","authors":"Kevin. V. Tobin PhD,&nbsp;Addison Pritchett MS,&nbsp;J. Steven Leeder PharmD, PhD,&nbsp;Joga Gobburu PhD,&nbsp;Allison Dunn PharmD","doi":"10.1002/jcph.70168","DOIUrl":"10.1002/jcph.70168","url":null,"abstract":"<p>Atomoxetine, a selective norepinephrine reuptake inhibitor, is a nonstimulant alternative to treat attention-deficit/hyperactivity disorder in children and adolescents. Atomoxetine exposure is highly variable due to cytochrome P450 polymorphism; however, the impact of these genetic variations has not been adequately characterized in the pediatric population. A population pharmacokinetic (PK) model was developed to evaluate steady-state atomoxetine exposures after oral administration in a large, heterogeneous population of children and adolescents with different metabolic phenotypes. Due to the highly variable and complex absorption between subjects and occasions, a two-stage approach was implemented, treating each participant/occasion as a separate individual. First, the individual atomoxetine parameters were estimated using a one-compartment distribution model with zero-order duration into a depot compartment followed by first-order absorption into the central compartment with linear elimination. Next, population-level parameters were obtained, and covariate analysis was performed. Using actual body weight, relative bioavailability based on CYP2D6 or CYP2C19 phenotype, and CYP2D6 clearance effects in the model reduced the variability from 81.6% to 64.5% and 92.4% to 75.5% for apparent volume and apparent clearance, respectively. The final model showed adequate precision in PK parameters and accuracy in exposure metrics. Following prospective validation, this model could be used to provide clinicians with individualized dosing targets when prescribing atomoxetine to children and adolescents based on their genetic disposition.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13033967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576039","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, Safety, and Tolerability of GS-1427, an Oral Prodrug of a Potent and Selective α4β7 Integrin Inhibitor, in Healthy Participants","authors":"Jin Zhou PhD,&nbsp;Neeraja Maramreddy MD,&nbsp;John McFarlane BSc,&nbsp;Yan Zhou PhD,&nbsp;Frank Hong MDPhD,&nbsp;Sandhya Girish PhD","doi":"10.1002/jcph.70177","DOIUrl":"10.1002/jcph.70177","url":null,"abstract":"<p>GS-1427 is the oral prodrug of GS-1069518, an inhibitor of the α4β7 integrin, and is currently in development for the treatment of ulcerative colitis (UC). This first-in-human, phase 1, placebo-controlled study evaluated the pharmacokinetics, safety, and tolerability of GS-1427 and GS-1069518 after single oral doses (20-1000 mg) or multiple once-daily doses (20-500 mg) of GS-1427 for 14 days. The bioavailability of tablet versus capsule formulations and the effect of food and an acid-reducing agent (omeprazole) on exposure were also assessed. Overall, 148 healthy participants were enrolled, and 143 completed the study. GS-1427 was quickly converted to GS-1069518 during absorption. Upon repeated once-daily dosing of GS-1427 under nonfasting conditions, steady-state exposure to GS-1069518 was reached by day 5 with limited accumulation observed. At steady state, the median time to maximum concentration for GS-1069518 was 1-3 h and the mean terminal half-life was 6.7-28.3 h. Bioavailability was lower in the tablet than in capsule formulation. Food intake and omeprazole coadministration reduced the exposure to GS-1069518 by approximately 20%-40%. Overall, 26/122 participants (21.3%) who received GS-1427 and 8/26 participants (30.1%) who received placebo experienced at least one treatment-emergent adverse event (AE). Of the 148 participants, 10 (6.8%) experienced a treatment-related AE, the most common being nausea (5/148, 3.4%) and diarrhea (3/148, 2.0%). All AEs were grade 1 in severity and no serious AEs or deaths were reported. The pharmacokinetics, safety, and tolerability results from this study support further evaluation of GS-1427 in a phase 2 trial in patients with UC.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147488041","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":"Invisible No More: How Redefining Rare Diseases Can Advance Health Equity","authors":"Rajesh Krishna PhD, MBA","doi":"10.1002/jcph.70179","DOIUrl":"10.1002/jcph.70179","url":null,"abstract":"&lt;p&gt;The prevailing definition of “rare diseases,” typically based on arbitrary prevalence or incidence thresholds, has become a policy tool that increasingly obscures reality and in some cases undermines equity in health systems. While these definitions are well intentioned and originally intended to facilitate regulation and research prioritization, they now function as blunt instruments that fail to reflect advances in diagnostics, clinical burden, societal impact, or scientific opportunity.&lt;/p&gt;&lt;p&gt;To better understand the historical context, some context setting is required. The decision to define rare diseases by prevalence was a pragmatic solution to a crisis in drug development that peaked in the 1970s. Prior to this reference point, “rare” was a clinical description, but it had no legal or economic weight. The transition to a numerical definition was driven by a movement of “medical refugees,” that is, patients whose conditions were known to science but ignored by industry.&lt;/p&gt;&lt;p&gt;This is because commercially inclined pharmaceutical industry focused on “blockbuster” drugs for common ailments like hypertension or infection. In that regard, small patient populations were deemed “unprofitable.” The “Orphan” metaphor gained traction in the 1960s and 1970s, when physicians began calling drugs for rare conditions “orphans” because they lacked a “parent” (a pharmaceutical sponsor) to bring them to market. The movement gained momentum when families of children with conditions like Tourette syndrome and Hemophilia began organizing. They realized the problem was not a lack of scientific interest, but a broken economic model. In the United States, the Waxman–Hatch discussions led to the Orphan Drug Act of 1983. This was the first time “rare disease” was codified into law. Originally, the 1983 Act did not even have a numerical definition. It simply defined a rare disease as one for which there was “no reasonable expectation” that the cost of development would be recovered from sales. This “lack of profit” definition proved too difficult to audit. To provide clarity for the FDA and industry, Congress amended the Act in 1984 to include a hard prevalence cap: fewer than 200,000 people in the United States.&lt;/p&gt;&lt;p&gt;Following the success of the US model, other regions adopted prevalence-based definitions to align with global R&amp;D pipelines, though the specific “cut-off” numbers varied based on population size and healthcare philosophy. During the drafting of these laws, policymakers debated using “severity” or “unmet need” as the metric. However, prevalence was chosen for three historical reasons: (1) prevalence provided a “bright line” for regulators. A disease either met the number or it did not, preventing endless litigation over how “severe” a condition truly was; (2) legislators viewed rare disease policy as a form of social insurance. Since anyone could be born with a rare mutation, the policy was designed to protect the &lt;i&gt;rarity&lt;/i&gt; of the event, muc","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70179","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147482167","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":"Construction and Validation of a Predictive Model for the Risk of Anti-Tuberculosis Drug-Induced Liver Injury Based on Machine Learning Algorithms","authors":"Jingru Cheng MSc,&nbsp;Ruina Chen MSc,&nbsp;Hongqiu Pan MSc,&nbsp;Lihuan Lu MSc,&nbsp;Meiling Zhang BSc,&nbsp;Xiaomin He MSc,&nbsp;Honggang Yi PhD,&nbsp;Shaowen Tang PhD","doi":"10.1002/jcph.70131","DOIUrl":"10.1002/jcph.70131","url":null,"abstract":"<p>Anti-tuberculosis drug-induced liver injury (ATLI) is the most harmful to anti-tuberculosis (TB) treatment. This study aims to construct and validate a binary ATLI risk prediction model based on clinical data through seven machine learning algorithms (logistic regression, decision tree, support vector machine, random forest, gradient boosting decision tree, extreme gradient boosting, and light gradient boosting machine [LightGBM]). A retrospective cohort of 2356 TB patients followed between January 2017 and December 2024 was used to develop and evaluate the prediction model. Random undersampling was performed to address class imbalance problem. Least absolute shrinkage and selection operator (LASSO) regression was used to select features and retained 27 of 31 original features. Seven ML algorithms were trained and the LightGBM model demonstrated optimal performance in testing set based on the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity (AUC = 0.789, sensitivity = 0.734, and specificity = 0.706). The model exhibited optimal simplicity and stability when incorporating the 8-feature combination comprising baseline high-density lipoprotein cholesterol (HDLC), γ-glutamyl transpeptidase (GGT), triglycerides, total cholesterol (TCHOL), uric acid, total bilirubin (TBIL), globulin (GLB), and liver disease history (AUC = 0.764, sensitivity = 0.758, and specificity = 0.610), and Shapely additive explanations analysis also revealed that these variables were the most influential contributors. The optimal model maintained robust predictive ability in the external validation cohort (AUC = 0.721, sensitivity = 0.828, and specificity = 0.604). This study determined that the combination of baseline HDLC, GGT, triglycerides, total cholesterol (TCHOL), uric acid, TBIL, GLB, and liver disease history was an important predictor of ATLI through LightGBM model, which could help clinicians in the early identification of ATLI.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145641757","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":"Celebrating the 65th Anniversary of the Journal of Clinical Pharmacology","authors":"John van den Anker MD, PhD, FCP, FAAP","doi":"10.1002/jcph.70173","DOIUrl":"10.1002/jcph.70173","url":null,"abstract":"&lt;p&gt;It is with great pleasure that I share with you that in 2026, the American College of Clinical Pharmacology (ACCP) is celebrating the 65th anniversary of the &lt;i&gt;Journal of Clinical Pharmacology&lt;/i&gt; (&lt;i&gt;JCP&lt;/i&gt;). On behalf of the President of the College, the Officers, the Board of Regents, the Publications Committee, and ACCP Staff, the JCP Editorial Team will publish three special issues of the journal this year.&lt;/p&gt;&lt;p&gt;I would like to introduce the first two of these special issues to you in this editorial; in September, I will dedicate a separate editorial to the third. We believed that it would be important to highlight important achievements associated with JCP and therefore have dedicated one special issue to the papers that received the McKeen Cattell Award and another to celebrate the most cited papers. The latter will publish papers that have been cited 175–498 times since 2010.&lt;/p&gt;&lt;p&gt;With regard to the first special issue, I would like to provide additional information about Dr. McKeen Cattell, the first JCP editor.&lt;/p&gt;&lt;p&gt;McKeen Cattell, MD, PhD, FCP, studied as an undergraduate at Columbia and Cambridge Universities, graduating from Columbia in 1914. He subsequently received a PhD in physiology from Harvard in 1920 and graduated from Harvard Medical School before joining the Department of Physiology at Cornell University Medical College in 1924. In 1937, he became Chairman of the Department of Pharmacology, where, with the late Drs. Harry Gold (a clinician and researcher in the Department of Pharmacology at Cornell Medical College) and Nathaniel T. Kwit (a clinician at Cornell), he carried out important clinical investigations involving both animal and human subjects. These studies established a firm scientific basis for the efficacy of digitalis glycosides in congestive heart failure.&lt;/p&gt;&lt;p&gt;In the late 1940s, Dr. Cattell was part of a group of medical scientists who convinced the Federal Government of the importance of basic biomedical research. He later served in several key advisory roles for the National Institutes of Health and as an adviser to committees of the New York Academy of Medicine.&lt;/p&gt;&lt;p&gt;He served as the Editor-in-Chief of &lt;i&gt;The Journal of the American Society for Pharmacology and Experimental Therapeutics&lt;/i&gt; from 1946 to 1950 and retired from Cornell as Professor of Pharmacology Emeritus in 1959. Dr. Cattell continued contributing to the field of clinical pharmacology by founding the &lt;i&gt;Journal of New Drugs&lt;/i&gt; in January 1961 and serving as its Editor for the next 6 years. In 1967, &lt;i&gt;JCP&lt;/i&gt; was established by Dr. Cattell, who served as its Editor for 10 years.&lt;/p&gt;&lt;p&gt;In collaboration with his colleagues Drs. Kwit and Gold, along with Drs. Duncan Hutcheon and Philip Reichert, Dr. Cattell became a founding father of the American College of Clinical Pharmacology, which was legally incorporated on September 11, 1969. The Articles of Incorporation list Drs. Duncan E. Hutcheon, McKeen Cattell, and Harry Gold as the init","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13011909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147379313","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":"Anthropometric Exclusions in Pediatric Clinical Trials: Implications for Medication Dosing in Malnourished Children","authors":"Susan M. Abdel-Rahman PharmD, MA,&nbsp;Sherbet Samuels PhD, MPH,&nbsp;Janie Cole PharmD,&nbsp;Gilbert J. Burckart PharmD","doi":"10.1002/jcph.70120","DOIUrl":"10.1002/jcph.70120","url":null,"abstract":"<p>Malnutrition occurs at higher rates in children with complex medical conditions and can independently influence drug disposition and action. Yet FDA-approved product labels rarely address dosing in malnutrition. This study explores the extent to which malnourished children are expressly excluded from clinical trials. Industry-sponsored, pediatric, phase I-III studies deposited in ClinicalTrials.Gov through December 2024 with a full study protocol were reviewed. Protocols were evaluated for inclusion and exclusion (I/E) criteria related to anthropometric and clinical indicators of malnutrition. I/E criteria were fully characterized along with the study phase, intervention type, and treatment indication. 9882 studies were identified, 1759 with an uploaded protocol. 616 studies (35%) contained 777 distinct I/E criteria related to malnutrition (1–6 per study). Across all protocols, 71% exclusively restricted participation of children with evidence of undernutrition, 9% with overnutrition, and 20% with both. There were no statistical differences observed based on intervention type, though differences by study phase were observed. Restrictions were seen most frequently for respiratory, mental/behavioral, obstetric/perinatal, and emergency use indications and least frequently for dermatologic, oncologic, and eyes, ears, nose, and throat disorders. Non-specific I/E criteria suggest that these findings likely underestimate the extent of malnutrition-based exclusions. Despite growing attention paid to obesity, pediatric clinical trials are far more likely to restrict the participation of undernourished children. Though unrealistic to relax malnutrition related I/E criteria for all studies, consideration should be given for conditions where high rates of malnutrition are expected to avoid trial populations that do not reflect clinical practice.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281586","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":"Evaluating the Impact of Linezolid Metabolites: PNU-142300 and PNU-142586 on the Development of Linezolid-Induced Thrombocytopenia in Adult Patients","authors":"Norihiro Sakurai PhD,&nbsp;Hiroshi Kawaguchi PhD,&nbsp;Toya Matsui BPharm,&nbsp;Hironobu Nishiura BPharm,&nbsp;Kazuhiro Kobayashi PhD,&nbsp;Waki Imoto MD, PhD,&nbsp;Wataru Shibata MD, PhD,&nbsp;Yasutaka Nakamura PhD,&nbsp;Hiroshi Kakeya MD, PhD","doi":"10.1002/jcph.70124","DOIUrl":"10.1002/jcph.70124","url":null,"abstract":"<p>Linezolid is a widely used antimicrobial agent in clinical practice; however, its usage is often limited by linezolid-induced thrombocytopenia (LIT). While prior studies have assessed linezolid plasma concentrations, the clinical relevance of its metabolites, PNU-142300 and PNU-142586, remains unclear. This study aimed to investigate the association between these metabolite concentrations and LIT, and to identify predictive thresholds. This study retrospectively analyzed patients treated with linezolid at Osaka Metropolitan University Hospital between January 2017 and December 2024. Patient characteristics, trough concentrations (C_trough), AUC₂₄, and pharmacokinetic parameters of linezolid and its metabolites were compared among patients with and without thrombocytopenia. Receiver operating characteristic (ROC) analysis identified thresholds for LIT prediction. Risk factors were assessed using multivariate logistic regression analysis. Forty-eight patients were included, with thrombocytopenia developing in 26 patients (54.2%). C_trough and AUC₂₄ of PNU-142300 and PNU-142586 were significantly higher in the thrombocytopenia group; meanwhile, linezolid C_trough and AUC₂₄ did not differ significantly. ROC analysis identified C_trough ≥1.43 µg/mL and AUC₂₄ ≥37.8 mg h/L for PNU-142586 as predictive thresholds. Multivariate analysis revealed that linezolid therapy ≥14 days (OR = 9.53, <i>P</i> = .044) and PNU-142586 C_trough ≥1.43 µg/mL (OR = 37.60, <i>P</i> = .002) as independent risk factors. Elevated PNU-142586 concentrations were associated with a higher cumulative incidence of LIT. Accumulation of linezolid metabolites, especially PNU-142586, is closely associated with LIT. Monitoring of PNU-142586 may improve the safety of linezolid therapy and support individualized dosing strategies.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145507763","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}