The Journal of Clinical Pharmacology最新文献

{"title":"Association of Gene Polymorphisms and Serum Levels of ALAS1 with the Risk of Anti‐Tuberculosis Drug‐Induced Liver Injury","authors":"Bing Han, Yiwen He, Min Zhu, Meiling Zhang, Lihuan Lu, Xiaoyan Xu, Xiaomin He, Honggang Yi, Shaowen Tang","doi":"10.1002/jcph.6137","DOIUrl":"https://doi.org/10.1002/jcph.6137","url":null,"abstract":"The accumulation of protoporphyrin IX in the liver caused by isoniazid and rifampicin through the disorder of heme biosynthesis was considered an important mechanism of anti‐tuberculosis drug‐induced liver injury (ATLI). Alanine synthase 1 (ALAS1) is a rate‐limiting enzyme in the process of heme synthesis. This study aimed to investigate the association between ALAS1 gene polymorphism, serum ALAS1 level, and the risk of ATLI. This study was a case‐control study including 58 ATLI cases and 192 controls. Four single nucleotide polymorphisms (SNPs) of the ALAS1 gene were selected for genotyping and serum ALAS1 concentrations were detected using ELISA kits. There was no significant difference in the genotype distribution of four SNPs between the ATLI cases and the controls under different genetic models. Patients carrying the GG genotype of SNP rs352163 in controls had higher baseline ALAS1 levels than those in ATLI cases (243.6 vs 290.2 ng/L, <jats:italic>P</jats:italic> = .034), and patients with baseline ALAS1 &lt; 337.85 ng/L had a higher risk of ATLI than those with ALAS1 ≥ 337.85 ng/L (HR = 2.679, 95% CI: 1.360‐5.278, <jats:italic>P</jats:italic> = .004). Our findings indicated that the serum ALAS1 concentrations in the ATLI cases were lower than those in the controls, and the lower baseline ALAS1 levels can be associated with higher ATLI risk.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251348","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":"Single‐Dose Tolerability and Pharmacokinetics of Onradivir in Chinese Patients with Hepatic Impairment and Healthy Matched Controls","authors":"Cuiyun Li, Haijun Li, Jiajia Mai, Hong Zhang, Min Wu, Yanhua Ding, Jufang Huang","doi":"10.1002/jcph.6134","DOIUrl":"https://doi.org/10.1002/jcph.6134","url":null,"abstract":"This study compared the safety and pharmacokinetics of a single oral dose of onradivir, an inhibitor of polymerase basic protein 2 in influenza A virus, in patients with hepatic impairment and healthy participants with normal hepatic function. Eight participants with mild hepatic impairment (Child‐Pugh A), eight participants with moderate hepatic impairment (Child‐Pugh B), and eight healthy matched controls were enrolled in this open‐label, parallel‐group clinical trial. After the administration of 600 mg of onradivir, pharmacokinetic parameters were calculated for each cohort and compared. Onradivir was generally well tolerated by all participants. No serious adverse events (AEs) and no deaths were reported during the study. Six patients with moderate hepatic impairment and three patients with mild hepatic impairment reported AEs, all of which were mild and quickly resolved. Compared with the normal liver function group, the maximum concentration, area under the curve from time zero to the last measurable concentration, and area under the curve from time zero to infinity were 103%, 68.5%, and 69.2% higher, respectively, in the mild hepatic impairment group. In the moderate hepatic impairment group, these increases were 101%, 197%, and 204%, respectively. Overall, there were clinically relevant differences in onradivir exposure between patients with mild or moderate hepatic impairment and normal controls. These data imply that onradivir dose adjustment is warranted in patients with mild or moderate hepatic impairment. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT05856513).","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251347","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":"Effect of Food on the Pharmacokinetics, Safety, and Tolerability of Budesonide Oral Suspension in Healthy Adult Participants: A Randomized Phase 1 Study","authors":"Alexander J. Prokopienko, Junyao Wang, Vijay Yajnik, Mike Baratta, Nirav K. Desai, Camilla A. Richmond, Ajit Suri","doi":"10.1002/jcph.6131","DOIUrl":"https://doi.org/10.1002/jcph.6131","url":null,"abstract":"Budesonide oral suspension (BOS) is a swallowed corticosteroid indicated for 12‐week therapy in eosinophilic esophagitis with minimal systemic exposure following administration. We aimed to assess the relative bioavailability of a single dose of BOS administered under fasting and fed (high‐fat/high‐calorie meal) conditions. Healthy adult volunteers (N = 20) were enrolled in an open‐label, single‐center, crossover study and were randomized (1:1) to receive a single oral dose of BOS 2.0 mg under fasting or fed conditions, with a 48‐h washout period before crossover to the alternative conditions. Serial plasma samples were collected before and up to 24 h after dosing. Pharmacokinetic (PK) parameters were calculated from plasma budesonide concentration–time profiles by noncompartmental analysis. The mean peak budesonide concentration (C<jats:sub>max</jats:sub>) was ∼13% lower under fed than under fasting conditions (604.1 vs 692.9 pg/mL). Areas under the concentration–time curves from dosing to the last measurable budesonide concentration and from dosing to infinity were ∼26% higher and ∼27% higher under fed than fasting conditions (3529 vs 2811 pg h/mL and 3892 vs 3075 pg h/mL, respectively). The median time to peak plasma budesonide concentration was significantly longer (∼1 h) under fed than fasting conditions (2.516 vs 1.286 h, <jats:italic>P</jats:italic> &lt; .001). Safety and tolerability were also assessed throughout the study; all adverse events were mild or moderate in severity. Despite slight differences in budesonide PK parameters between fed and fasting conditions, the effect of food on systemic exposure to budesonide (BOS formulation) is not expected to be clinically meaningful.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178395","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":"Population Pharmacokinetics of Xeligekimab: An Anti‐IL‐17A Monoclonal Antibody, in Patients with Moderate to Severe Plaque Psoriasis","authors":"Qingheng Meng, Wei Wang, Lingxiao Zhang, Haiyang Shi, Hongxia Liu, Qingshan Zheng, Ling Xu","doi":"10.1002/jcph.6129","DOIUrl":"https://doi.org/10.1002/jcph.6129","url":null,"abstract":"Xeligekimab, a recombinant fully human IgG4 monoclonal antibody, has been strategically developed to target IL‐17A and is presently in the developmental phase for treating moderate to severe plaque psoriasis. This study aims to investigate the pharmacokinetic profile of Xeligekimab, utilizing data derived from clinical trials specifically conducted in Chinese patients. The study conducted a population pharmacokinetic (PopPK) analysis involving 614 patients with plaque psoriasis. Examined covariates encompassed demographics, baseline laboratory tests, anti‐drug antibodies (ADA), injection site, and disease‐related baseline characteristics. Model evaluation utilized goodness‐of‐fit, prediction‐corrected visual prediction check, and bootstrap methods. The clinical significance of covariates statistically associated with Xeligekimab was assessed through simulation analysis. The PopPK model of Xeligekimab demonstrated characteristics of a two‐compartment model with first‐order absorption and linear elimination. Inter‐individual variability (IIV) was estimated for clearance and volume of distribution. For a typical plaque psoriasis patient, the estimated values for absorption rate constant (Ka), apparent clearance (CL/F), central compartment volume (V<jats:sub>c</jats:sub>/F), peripheral compartment volume (V<jats:sub>p</jats:sub>/F), and inter‐compartmental clearance (Q/F) was 0.225 per day, 2.223 L/day, 4.02 L, 4.13 L, and 1.11 L/day, respectively. The estimated IIV for CL/F and V<jats:sub>c</jats:sub>/F was 25.8% and 49.8%, respectively. The elimination half‐life (t<jats:sub>1/2</jats:sub>) was approximately 28.5 days. CL/F was significantly influenced by factors such as body weight, age, gender, and baseline total protein. V<jats:sub>c</jats:sub>/F was significantly influenced by body weight, age, gender, and baseline albumin. However, the clinical relevance of these covariate effects on exposure parameters was determined to be limited.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178397","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":"Correction to “The Association Between Concurrence of Infection and the Onset of Severe Eruption or Liver Injury in Patients Using Antipyretic Analgesics: A Matched, Nested Case-Control Study”","authors":"","doi":"10.1002/jcph.2497","DOIUrl":"10.1002/jcph.2497","url":null,"abstract":"<p>Imatoh T, Sai K, Saito Y. The association between concurrence of infection and the onset of severe eruption or liver injury in patients using antipyretic analgesics: a matched, nested Case-Control study. J Clin Pharmacol. 2020;60(9):1177-1184. doi:10.1002/jcph.1613</p><p>In variable “index year” within Table 3, the number of cases and controls were incorrect. A table with excerpts of the revised portions (“Index year”) is indicated below.\u0000\u0000 </p><p>We apologize for this error.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2497","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074278","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":"Exposure–Response Modeling in Adults and Adolescents With Schizophrenia to Support the Extrapolation of Brexpiprazole Efficacy to Adolescents","authors":"Xiaofeng Wang PhD,&nbsp;Mathangi Gopalakrishnan PhD,&nbsp;Benjamin Rich PhD,&nbsp;Jogarao V. Gobburu PhD,&nbsp;Frank Larsen PhD,&nbsp;Arash Raoufinia PharmD","doi":"10.1002/jcph.2464","DOIUrl":"10.1002/jcph.2464","url":null,"abstract":"<p>In order to accelerate drug development and avoid unnecessary drug trials in vulnerable pediatric populations, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents. Extrapolation is based on the evidence-based assumptions that (1) disease characteristics and (2) response to therapy, are similar in adults and adolescents. Whereas the FDA validated the extrapolation approach using data from multiple drug development programs, aripiprazole data are the most relevant to confirm the validity of the extrapolation approach for brexpiprazole, since aripiprazole and brexpiprazole both modulate dopaminergic and serotonergic signaling in the brain. The aims of this analysis were (1) to quantitatively assess the aripiprazole exposure (average steady-state concentration)–response (Positive and Negative Syndrome Scale total score change from baseline) similarity between adults and adolescents with schizophrenia, (2) to extend the aripiprazole exposure–response modeling to brexpiprazole using adult data, and (3) to use the brexpiprazole model to predict schizophrenia symptom response in adolescents. Disease–drug–dropout models were developed using patient-level data from clinical studies of aripiprazole (1007 adults, 294 adolescents) and brexpiprazole (1235 adults) in schizophrenia. The aripiprazole model demonstrated similar exposure–response between adults and adolescents with schizophrenia, validating the extrapolation approach. Extrapolation of the brexpiprazole adult exposure–response model to adolescents predicted the efficacy of brexpiprazole in adolescents aged 13-17 years with schizophrenia.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2464","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141555785","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":"ACCP Position Statement on Unregulated Psychotropic Products","authors":"Tao Long PhD,&nbsp;Sindura Gollamudi MS,&nbsp;Sudhakar Pai PhD, FCP,&nbsp;the ACCP Public Policy Committee","doi":"10.1002/jcph.2485","DOIUrl":"10.1002/jcph.2485","url":null,"abstract":"","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494007","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":"Pharmacotherapy of Weight-loss and Obesity with a Focus on GLP 1-Receptor Agonists","authors":"Merle Myerson MD, EdD,&nbsp;Rodis D. Paparodis MD, FNLA","doi":"10.1002/jcph.2487","DOIUrl":"10.1002/jcph.2487","url":null,"abstract":"<p>Obesity is a disease of epidemic proportions in the United States and contributes to morbidity and mortality for a large part of the population. In addition, the financial costs of this disease to society are high. Lifestyle modifications are key to prevention and treatment but adherence and long-term success have been challenging. Bariatric surgery has been available and pharmacologic approaches, first developed in the 1950s, continue to be an option; however, existing formulations have not provided optimal clinical efficacy and have had many concerning adverse effects. Over the last decade, glucagon-like peptide-1 (GLP-1) receptor agonists, a novel group of medications for the treatment of type 2 diabetes, were found to produce significant weight loss. Several formulations, at higher doses, received FDA approval for the treatment of obesity or those overweight with weight-related co-morbidities. More hormone-based therapies were and are being developed, some with dual or triple-receptor agonist activity. Their use, however, is not without questions and concerns as to long-term safety and efficacy, problems with cost and reimbursement, and how their use may intersect with public health efforts to manage the obesity epidemic. This review will focus on the GLP-1 receptor agonists currently used for weight loss and discuss their pharmacology, pertinent research findings establishing their benefits and risks, issues with prescribing these medications, and a perspective from a public health point of view.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460110","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":"A big thank you and a warm welcome","authors":"John N. van den Anker MD, PhD","doi":"10.1002/jcph.2489","DOIUrl":"10.1002/jcph.2489","url":null,"abstract":"<p>On July 1, 2024, we will say goodbye to Dion Brocks, James Burris, Monette Cotreau, Michael Court, Vera Donnenberg, Kerry Estes, Michael Jann, William Jusko, Adel Karara, Jing Li, Melanie Nicol, George Perentesis, Mark Ratain, Catherine Sherwin, Antonio Tugores, and John Wagner as outgoing members of the Editorial Board of the Journal of Clinical Pharmacology (JCP). On behalf of the American College of Clinical Pharmacology (ACCP), I would like to profusely thank all of them for their outstanding service as Editorial Board members and sincerely hope they will continue to serve as peer reviewers for the Journal as well as submit their best original and review work to JCP for many years to come.</p><p>At the same time, I am excited to extend a warm welcome to our newly appointed Editorial board members Karel Allegaert, Luke Baxter, David Burger, Carter Cao, Ayyappa Chaturvedula, Andre Dallmann, Elimika Pfuma Fletcher, Verena Gotta, Navin Goyal, Hazem Hassan, Chuanpu Hu, Zheng Jiao, Gilbert Koch, Don Mager, Cody Peer, Ana Ruiz-Garcia, Sinno Simons, Janelle Vaughns, Wei Zhao, and Victoria Ziesenitz.</p><p>It is important to emphasize that members of the Editorial Board not only have an extremely important role in enhancing the scientific quality of the Journal but also carry an important responsibility in strategically supporting the growth of the Journal. To succeed in reaching these goals, an efficient, effective, and collegial collaboration between members of the Editorial Board, the Chair and Members of the ACCP's Publications Committee, ACCP staff, the Senior Managing and Associate Managing Editors, the Publisher, the Associate Editors, and Editor-in-Chief is absolutely necessary.</p><p>The future of JCP is bright and promising. Several initiatives such as the development of graphical and video abstracts, plain language summaries, and, last but not least, mentoring of new and junior peer reviewers, are either ongoing or under active deliberations. In addition to actively contributing to the success of these exciting initiatives, we count on the Editorial Board members to provide constructive suggestions on how we can collectively improve the quality and global visibility and impact of our Journal. I have unequivocal and unwavering confidence in the strengths of this outstanding Editorial Board and am looking forward to receiving their innovative and creative ideas in the near future.</p><p>There are also worrisome issues that deserve our immediate and undivided attention. Let us start with the most gruesome one of those: fake science. One of the sources of propagating and promoting fake science is the worrisome emergence of entities colloquially referred to as “paper mills.” One of the modus operandi of such businesses or individuals is to list a scientist as an author of a wholly or partially fabricated paper. The “mill” will then submit the work, generally avoiding the most prestigious journals in favor of journals whose peer review process","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2489","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460111","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":"Development and Evaluation of Ontogeny Functions of the Major UDP-Glucuronosyltransferase Enzymes to Underwrite Physiologically Based Pharmacokinetic Modeling in Pediatric Populations","authors":"Nashid Farhan PhD,&nbsp;Upendra P. Dahal PhD,&nbsp;Jan Wahlstrom PhD","doi":"10.1002/jcph.2484","DOIUrl":"10.1002/jcph.2484","url":null,"abstract":"<p>Uridine 5′-diphospho-glucuronosyltransferases (UGTs) demonstrate variable expression in the pediatric population. Thus, understanding of age-dependent maturation of UGTs is critical for accurate pediatric pharmacokinetics (PK) prediction of drugs that are susceptible for glucuronidation. Ontogeny functions of major UGTs have been previously developed and reported. However, those ontogeny functions are based on in vitro data (i.e., enzyme abundance, in vitro substrate activity, and so on) and therefore, may not translate to in vivo maturation of UGTs in the clinical setting. This report describes meta-analysis of the literature to develop and compare ontogeny functions for 8 primary UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B10, UGT2B15, and UGT2B17) based on published in vitro and in vivo studies. Once integrated with physiologically based pharmacokinetics modeling models, in vivo activity-based ontogeny functions demonstrated somewhat greater prediction accuracy (mean squared error, MSE: 0.05) compared to in vitro activity (MSE: 0.104) and in vitro abundance-based ontogeny functions (MSE: 0.129).</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141428043","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}