Clinical Pharmacology & Therapeutics最新文献

{"title":"Population-Based Validation Results From the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) Study","authors":"Rishi J. Desai,&nbsp;Vijay R. Varma,&nbsp;Mufaddal Mahesri,&nbsp;Su Been Lee,&nbsp;Ariel Freedman,&nbsp;Tobias Gerhard,&nbsp;Jodi Segal,&nbsp;Seanna Vine,&nbsp;Mary Beth E. Ritchey,&nbsp;Daniel B. Horton,&nbsp;Madhav Thambisetty","doi":"10.1002/cpt.3583","DOIUrl":"10.1002/cpt.3583","url":null,"abstract":"<p>We evaluated whether drugs approved for other indications that also target metabolic drivers of Alzheimer's disease and related dementia (ADRD) pathogenesis are associated with delayed onset of ADRD. Using routinely collected healthcare data from two population-based data sources from the US (Medicare) and UK (CPRD), we conducted active comparator, new-user cohort studies. Four alternate analytic and design specifications were implemented: (1) an as-treated follow-up approach, (2) an as-started follow-up approach incorporating a 6-month induction period, (3) incorporating a 6-month symptom to diagnosis period to account for misclassification of ADRD onset, and (4) identifying ADRD through symptomatic prescriptions and diagnosis codes. Of the 10 drug pairs evaluated, hydrochlorothiazide vs. dihydropyridine CCBs showed meaningful reductions in 3 out of 4 analyses that addressed specific biases including informative censoring, reverse causality, and outcome misclassification (pooled hazard ratios [95% confidence intervals] across Medicare and CPRD: 0.81 [0.75–0.88] in Analysis 1, 0.98 [0.92–1.06] in Analysis 2, 0.83 [0.75–0.91] in Analysis 3, 0.75 [0.65–0.85] in Analysis 4). Amiloride vs. triamterene, although less precise, also suggested a potential reduction in risk in 3 out of 4 analyses (0.86 [0.66–1.11] in Analysis 1, 0.98 [0.79–1.23] in Analysis 2, 0.74 [0.54–1.00] in Analysis 3, 0.61 [0.36–1.05] in Analysis 4). Other analyses suggested likely no major differences in risk (probenecid, salbutamol, montelukast, propranolol/carvedilol, and anastrozole) or had limited precision precluding a definitive conclusion (semaglutide, ciloztozol, levetiracetam). Future replication studies should be considered to validate our findings.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 4","pages":"1039-1050"},"PeriodicalIF":6.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chat GPT vs. Clinical Decision Support Systems in the Analysis of Drug–Drug Interactions","authors":"Thorsten Bischof,&nbsp;Valentin al Jalali,&nbsp;Markus Zeitlinger,&nbsp;Anselm Jorda,&nbsp;Michelle Hana,&nbsp;Karla-Nikita Singeorzan,&nbsp;Nikolaus Riesenhuber,&nbsp;Gunar Stemer,&nbsp;Christian Schoergenhofer","doi":"10.1002/cpt.3585","DOIUrl":"10.1002/cpt.3585","url":null,"abstract":"<p>The current standard method for the analysis of potential drug–drug interactions (pDDIs) is time-consuming and includes the use of multiple clinical decision support systems (CDSSs) and the interpretation by healthcare professionals. With the emergence of large language models developed with artificial intelligence, an interesting alternative arose. This retrospective study included 30 patients with polypharmacy, who underwent a pDDI analysis between October 2022 and August 2023, and compared the performance of Chat GPT and established CDSSs (MediQ®, Lexicomp®, Micromedex®) in the analysis of pDDIs. A multidisciplinary team interpreted the obtained results and decided upon clinical relevance and assigned severity grades using three categories: (i) contraindicated, (ii) severe, (iii) moderate. The expert review identified a total of 280 clinically relevant pDDIs (3 contraindications, 13 severe, 264 moderate) using established CDSSs, compared with 80 pDDIs (2 contraindications, 5 severe, 73 moderate) using Chat GPT. Chat GPT almost entirely neglected pDDIs with the risk to QTc prolongation (85 vs. 8), which could also not be sufficiently improved by using a specific prompt. To assess the consistency of the results provided by Chat GPT, we repeated each query and found inconsistent results in 90% of the cases. In contrast, Chat GPT provided acceptable and comprehensible recommendations for specific questions on side effects. The use of Chat GPT for the identification of pDDIs cannot be recommended currently, because clinically relevant pDDIs were not detected, there were obvious errors and results were inconsistent. However, if these limitations are addressed accordingly, it is a promising platform for the future.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 4","pages":"1142-1147"},"PeriodicalIF":6.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimal Dosing Regimen for Epcoritamab, a Subcutaneous Bispecific Antibody, in Relapsed or Refractory Large B-Cell Lymphoma","authors":"Tommy Li,&nbsp;Leonid Gibiansky,&nbsp;Apurvasena Parikh,&nbsp;Matthew Putnins,&nbsp;Christopher W. Chiu,&nbsp;Mariana Sacchi,&nbsp;Huaibao Feng,&nbsp;Tahamtan Ahmadi,&nbsp;Manish Gupta,&nbsp;Steven Xu","doi":"10.1002/cpt.3588","DOIUrl":"10.1002/cpt.3588","url":null,"abstract":"<p>Epcoritamab is a CD3xCD20 bispecific antibody that activates T cells to kill CD20-expressing B cells. Epcoritamab is approved for the treatment of adults with different types of relapsed or refractory lymphoma in various geographies, including the United States, Europe, and Japan. Epcoritamab demonstrated an overall response rate of 63%, a complete response rate of 39%, and manageable safety with the approved dosing regimen (0.16-mg and 0.8-mg step-up doses and 48-mg full dose, with dosing every week in cycles 1–3, every 2 weeks in cycles 4–9, and every 4 weeks in cycles ≥ 10) in patients with relapsed or refractory large B-cell lymphoma from the phase 1/2 EPCORE® NHL-1 trial expansion through January 31, 2022. Exposure–efficacy analyses including the EPCORE NHL-1 and EPCORE NHL-3 trials revealed that higher exposure was associated with a higher overall response rate, complete response rate, progression-free survival, and overall survival. A potential plateau of efficacy was observed at 48 mg or above. The exposure–safety analyses of these trials did not identify any safety concerns with the approved dosing regimen. No associations were detected between exposure and safety endpoints. The step-up doses were clinically active and helped mitigate cytokine release syndrome risk at the subsequent full doses. Most initial responses (94%) were observed during the weekly dosing period, and most responders with large B-cell lymphoma maintained or improved their response during every 2 weeks and every 4 weeks dosing. Overall, these analyses support the approved single-agent epcoritamab 0.16/0.8/48-mg dosing regimen in relapsed or refractory large B-cell lymphoma.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 5","pages":"1437-1450"},"PeriodicalIF":6.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3588","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimal Drug, Optimal Dose, or Both in the Pharmacological Treatment of Neonatal Opioid Withdrawal Syndrome?","authors":"Walter K. Kraft","doi":"10.1002/cpt.3600","DOIUrl":"10.1002/cpt.3600","url":null,"abstract":"&lt;p&gt;The drugs and drug dose regimens used to treat opioid withdrawal symptoms in newborns with in utero opioid exposure have been developed in a mostly empiric fashion. Clonidine has long been used as an adjunct but has been explored as part of an opioid-free approach to primary therapy. The tools of pharmacometrics can provide a path for rational exploration of drug exposure and response.&lt;/p&gt;&lt;p&gt;Antenatal opioid exposure results in post-natal neonatal opioid withdrawal syndrome (NOWS) with cardinal symptomatology in the central and autonomic nervous systems and the gastrointestinal tract. The natural history of NOWS is characterized by an initial increase in symptoms as placentally transferred opioids are cleared from the infant's system. The therapeutic focus in treating newborns is on the reduction in symptom severity, with a goal of ensuring normal infant growth and development and maternal–infant bonding. Rates of NOWS have risen 7-fold over the past 20 years, and in parallel, there has been progress in therapeutic approaches to improving neonatal outcomes. Supportive measures with functional-based symptom assessment control symptoms for many infants. Non-pharmacologic measures have been standardized and refined, and their systematic implementation has reduced the number of infants requiring pharmacologic treatment. This has been an advantage since while pharmacologic treatment controls symptoms, it is associated with prolonged hospital stays and can impair maternal infant bonding. Clonidine is currently used as a rescue therapy in NOWS. The parent trial of Bada&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; (NCT03396588) tested the contrarian hypothesis that clonidine can improve outcomes for those requiring pharmacologic treatment compared with the current standard of opioid replacement using oral morphine. NOWS investigations are often difficult to interpret due to suboptimal design, such as before/after quality improvement programs that implement a suite of interventions, making the impact of any single action hard to assess. Retrospective&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; or single-arm studies with historical controls&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; are subject to differences in NOWS incidence or temporal changes in of maternal drug exposure such as the emergence of fentanyl. In contrast, the Bada study was large (for NOWS investigations), randomized, and blinded. All of these helped to mitigate the temporal bias of fentanyl use patterns as well as the difficult to predict impact of the COVID-19 pandemic. Importantly, the clinical data were magnified by the use of rich pharmacokinetic (PK) collection sampling, outlined in the work of Tang.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; External validity of the work is strengthened by parameter estimates congruent with both adult IV administration and the prior work of Xie in NOWS patients.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Simulations provided a number of options to consider in future investigations. Critically, the work is welcomed in moving improvements ","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 5","pages":"1182-1184"},"PeriodicalIF":6.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3600","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Model-Informed Selection of the Recommended Phase 2 Dosage for Anti-TIGIT Immunotherapy Leveraging co-Expressed PD-1 Inhibitor Target Engagement","authors":"Irina Kareva,&nbsp;Ping Hu,&nbsp;Vadryn Pierre,&nbsp;Thomas Kitzing,&nbsp;Anja Victor,&nbsp;Emilia Richter,&nbsp;Wei Gao,&nbsp;Karthik Venkatakrishnan,&nbsp;Anup Zutshi","doi":"10.1002/cpt.3590","DOIUrl":"10.1002/cpt.3590","url":null,"abstract":"<p>Refining dose projections requires a deep understanding of drug-target relationships at the site of action, which is often challenging to achieve. Here we present a case study of how one can refine dose projections for a TIGIT-targeted immunotherapy by leveraging information from the well-studied PD-1 pathway since the co-expression of PD-1 and TIGIT on immune cells provides a unique opportunity to extrapolate data from one target to inform the dosing strategy for the other. We develop a fit-for-purpose mathematical model that captures the experimentally observed relationship between the concentration of a mouse PD-1 antagonist in the plasma and PD-1 target engagement within the tumor microenvironment (TME). We then assess the applicability of this PD-1 model to elucidate the relationship between drug concentration and target engagement for tiragolumab, an anti-TIGIT antibody, across various doses. This analysis aims to refine our understanding of the dose–response relationship for targeting TIGIT, a critical step in optimizing therapeutic efficacy, without conducting additional experiments. The approach is then extended to project efficacious doses for M6223, another anti-TIGIT antibody, using the established PD-1 model, by leveraging the M6223 clinical PK and PD data, as well as virtual population analysis. This work provides a case study of a possible framework for refining dose projections via quantitative estimation of drug-target relationship at the site of action by leveraging established drug-target relationships. Through extrapolating information from a well-characterized pathway, we offer a method to inform dose optimization strategies with limited data using model-informed drug development.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 5","pages":"1451-1459"},"PeriodicalIF":6.3,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3590","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IQ Survey Results on Current Industry Practices: Part 2-Quantitative Evaluations of Immunogenicity Assessment.","authors":"Susan Richards, Insa Winzenborg, Doreen Luedtke, Tao Niu, Lora Hamuro, Karey Kowalski, Jocelyn H Leu, Jianning Yang, Vaishnavi Ganti, Indranil Bhattacharya, Ivelina Gueorguieva, Nael Mostafa, Christine Grimaldi, Benjamin Wu","doi":"10.1002/cpt.3573","DOIUrl":"https://doi.org/10.1002/cpt.3573","url":null,"abstract":"<p><p>All biotherapeutics have the potential to induce an immunogenic response and generate anti-drug antibodies (ADAs), especially when administered as multiple doses over prolonged periods. However, a clinically meaningful effect of ADAs can be difficult to identify to communicate the impact of immunogenicity on drug exposure, safety and efficacy outcomes in product labels in a way that is useful for health care providers. The immunogenicity working Group, IQ Consortium (Clinical Pharmacology Leadership Group) has conducted a survey to understand the current practices in analyzing immunogenicity data generated during clinical development and its impact on pharmacokinetics, clinically relevant pharmacodynamic biomarkers, safety, and efficacy outcome measures. Information was collected for 93 drugs, spanning multiple drug classes and over the different phases of clinical development, including post-approval. The predominant drug classes reported included monoclonal antibodies or Fc-fusion proteins, endogenous protein replacement therapies, bispecific antibodies, and antibody-drug conjugates. The extent of quantitative evaluation varied and was influenced by several factors, including descriptive analyses, statistical approaches, and modeling. In addition to understanding current practices, this survey also highlights areas for future exploration in analyzing clinical relevance of ADAs which can facilitate the use for regulatory submissions and product labels.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Effectiveness of First-Line Pembrolizumab vs. Chemotherapy in aNSCLC: A Norwegian Population-Based Cohort Study","authors":"Simon Boge Brant,&nbsp;Siri Børø,&nbsp;Christian Jonasson,&nbsp;Åslaug Helland,&nbsp;Steinar Thoresen","doi":"10.1002/cpt.3591","DOIUrl":"10.1002/cpt.3591","url":null,"abstract":"<p>The KEYNOTE-042^1,2 trial showed the benefit of treating patients with non-oncogene addicted advanced NSCLC with PD-L1 tumor proportion score over 50% with pembrolizumab as monotherapy over platinum-doublet chemotherapy. To contextualize these results, we undertake a detailed emulation of the inclusion criteria in KEYNOTE-042 using Norwegian health registry data and discuss both the clinical contexts, as well as the general utility of such registry data for pharmacoepidemiologic research in oncology. Within the population of patients with PD-L1 tumor proportion score over 50%, an observational analog of an intention-to-treat analysis showed similar results to those of the KEYNOTE-042 study.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 4","pages":"1123-1130"},"PeriodicalIF":6.3,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Model-Based Prediction of Clinically Relevant Thrombocytopenia after Allogeneic Hematopoietic Stem Cell Transplantation","authors":"Katharina M. Götz,&nbsp;Amin T. Turki,&nbsp;Katharina Och,&nbsp;Dominik Selzer,&nbsp;Christian Brossette,&nbsp;Norbert Graf,&nbsp;Jochen Rauch,&nbsp;Stefan Theobald,&nbsp;Yvonne Braun,&nbsp;Kerstin Rohm,&nbsp;Gabriele Weiler,&nbsp;Simeon Rüdesheim,&nbsp;Matthias Schwab,&nbsp;Lisa Eisenberg,&nbsp;Nico Pfeifer,&nbsp;Stephan Kiefer,&nbsp;Ulf Schwarz,&nbsp;Claudia Riede,&nbsp;Sigrun Smola,&nbsp;Dietrich W. Beelen,&nbsp;Dominic Kaddu-Mulindwa,&nbsp;Jürgen Rissland,&nbsp;Jörg Bittenbring,&nbsp;Thorsten Lehr","doi":"10.1002/cpt.3580","DOIUrl":"10.1002/cpt.3580","url":null,"abstract":"<p>Platelet reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT) is heterogeneous and influenced by various patient- and transplantation-related factors, associated with poor prognoses for poor graft function (PGF) and isolated thrombocytopenia. Tailored interventions could improve the outcome of patients with PGF and post-HCT thrombocytopenia. To provide individual predictions of 180-day platelet counts from early phase data, we developed a model of long-term platelet reconstitution after allo-HCT. A large cohort (<i>n</i> = 1949) of adult patients undergoing their first allo-HCT was included. Real-world data from 1,048 retrospective patients were used for non-linear mixed-effects model development. Bayesian forecasting was used to predict platelet–time profiles for 518 retrospective and 383 prospective patients during internal and external model validation, respectively. Thrombocytopenia was defined as mean platelet count &lt; 75 × 10⁹/L, derived from the last 12 platelet measurements within the first 180 days post-HCT. Thrombocytopenia affected 37% of all patients and was associated with significantly reduced overall survival (<i>P</i>-value &lt; 0.0001). On days +7, +14, +21, and +28, the developed model achieved areas under the receiver-operating characteristic of ≥ 0.68, ≥ 0.75, ≥ 0.78, and 0.81 for the prediction of post-HCT thrombocytopenia, respectively, with anti-thymocyte globulin, donor relation, and total protein measurements representing prognostic markers for post-HCT platelet kinetics. A publicly accessible web-based demonstrator of the model was established (https://hsct.precisiondosing.de). In summary, the developed model predicts individual platelet counts from day +28 post-HCT adequately, utilizing internal and external datasets. The web-based demonstrator provides a basis to implement model-based predictions in clinical practice and to confirm these findings in future clinical studies.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 5","pages":"1413-1426"},"PeriodicalIF":6.3,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3580","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role and Mechanisms of Aurora Kinases in Kidney Diseases","authors":"Meiying Chang,&nbsp;Qiuyi Li,&nbsp;Zhenwei Shi,&nbsp;Shougang Zhuang","doi":"10.1002/cpt.3584","DOIUrl":"10.1002/cpt.3584","url":null,"abstract":"<p>Aurora kinases are a family of serine/threonine kinases that includes Aurora kinase A, Aurora kinase B, and Aurora kinase C. These kinases play crucial roles in mitotic spindle formation and cell proliferation. Over the past several decades, extensive research has elucidated the multifaceted roles of Aurora kinases in cancer development and progression. Recent studies have also highlighted the significant involvement of Aurora kinases in various kidney diseases, such as renal cell carcinoma, diabetic nephropathy, chronic kidney disease, and polycystic kidney disease. The mechanisms by which Aurora kinases contribute to renal diseases are complex and influenced by both specific pathological conditions and environmental factors. In this review, we comprehensively summarize the role and mechanisms through which Aurora kinases operate in kidney diseases and discuss the efficacy and application of existing inhibitors targeting these kinases in managing renal disorders in animal models.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 5","pages":"1217-1225"},"PeriodicalIF":6.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Country Contribution to Investigators of Pivotal Clinical Trials and Their Primary Publications of New Drugs Approved by the US Food and Drug Administration, 2012–2021","authors":"Yoona Choi,&nbsp;Jung-Hyun Won,&nbsp;Heeju Kim,&nbsp;YeSol Hong,&nbsp;Yujin Kim,&nbsp;Howard Lee","doi":"10.1002/cpt.3589","DOIUrl":"10.1002/cpt.3589","url":null,"abstract":"<p>Pivotal clinical trials (PCTs) are often conducted across multiple nations and regions to achieve geographic, racial, or ethnic diversity. However, the diversity of PCT participants remains inadequate. PCTs for new drugs approved by the US Food and Drug Administration in 2012–2021 and their primary publications (PPub) were identified from the label and review documents. The country information about the PCT investigators and PPub authors were extracted from the PPubs or clinicaltrials.gov. The racial/ethnic diversity of PCT participants as reported in PPubs was assessed using the Diversity Index (DI). For 429 new drugs, 734 PCTs and 718 PPubs were identified. North America and Western Europe (NAWE) contributed the largest proportion of PCT investigators, PPub authors, and lead authors (62.9%, 81.7%, and 90.9%, respectively). Of 521 PPubs that reported the racial/ethnic distribution of PCT participants, the median DI was low at 0.33 (interquartile range 0.18–0.46) and only 16.3% PPubs had a DI &gt;0.5. The number of PPub authors in non-NAWE and the number of countries of PPub authors in non-NAWE was significantly associated with the racial/ethnic diversity of PCT participants (OR 1.17 [95% CI 1.08–1.26] and OR 1.25 [1.08–1.46], respectively). Evidence generation for the regulatory approval of new drugs has been predominantly centered in NAWE. The dominance is even more pronounced in the authorship of PPubs. To improve the racial/ethnic diversity of PCT participants, investigators from non-NAWE countries should be encouraged to play more leadership roles, thereby increasing their likelihood of serving as authors in PPub.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 4","pages":"1131-1141"},"PeriodicalIF":6.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}