Clinical Pharmacology & Therapeutics最新文献

{"title":"Distribution Characteristics and Impacting Factors of Drug CYP Enzymes and Transporters in the Gastrointestinal Tract of Chinese Healthy Subjects.","authors":"Miao Zhang, Lei Zhang, Baojun Suo, Yudong Wei, Yue Xu, Muhan Jiang, Jing Dong, Xiaodong Li, Zhiqiang Song, Dongyang Liu","doi":"10.1002/cpt.3497","DOIUrl":"https://doi.org/10.1002/cpt.3497","url":null,"abstract":"<p><p>The abundance of drug metabolic enzymes (DMEs) and transporters (DTs) in the human gastrointestinal tract significantly affects xenobiotic exposure in the circulating system, the basis of these compounds acting on humans. However, accurately predicting individual exposure in healthy subjects remains challenging due to limited data on protein levels throughout the gastrointestinal tract within the same individuals and inadequate assessment of factors influencing these levels. Therefore, we conducted a clinical study to obtain biopsy samples from 8 different gastrointestinal segments in 24 healthy Chinese volunteers. Concurrently, blood and fecal samples were collected for genotypic analysis and fecal microbiota metagenomic sequencing. Using an optimized LC-MS/MS method, we quantified the absolute protein abundance of CYP2C9, CYP2C19, CYP2D6, CYP3A4, P-gp, and BCRP from the stomach to the colon. Our results revealed significant regional differences in protein expression: CYP3A4 was the most abundant in the small intestine, whereas CYP2C9 was predominantly found in the colon. CYP2D6 was primarily located in the ileum, while other DMEs/DTs showed higher concentrations in the jejunum. Meanwhile, the enzyme abundance in the small intestine and colon and the relative ratio of transporters in different regions to the jejunum were accurately calculated, providing valuable data for refining the physiological parameters in the virtual gastrointestinal tract of Chinese healthy population in PBBMs. Additionally, BMI, IBW, sex, age, genotype, and fecal microbiota were identified as critical factors influencing the protein levels of these DMEs/DTs throughout the gastrointestinal tract, with notable regional differences. Consequently, this study provides a unique foundation for understanding xenobiotic absorption in humans.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708760","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":"Pharmacokinetic Modeling and Model-Based Hypothesis Generation for Dose Optimization of Clonidine in Neonates With Neonatal Opioid Withdrawal Syndrome.","authors":"Fei Tang, Chee M Ng, Jamie Horn, Henrietta S Bada, Markos Leggas","doi":"10.1002/cpt.3507","DOIUrl":"10.1002/cpt.3507","url":null,"abstract":"<p><p>The No-POPPY study (NCT03396588), a double-blind, randomized trial compared morphine with clonidine therapy for neonatal opioid withdrawal syndrome (NOWS) and found that the duration of treatment was similar across groups. This is significant because perinatal use of morphine has the potential for neurodevelopmental consequences. Still, the clonidine group reached symptom stabilization (Finnegan score (FS) < 8) later than the morphine group and had a more significant number of patients who required adjunct therapy. However, the mean FS was consistently lower in the clonidine group after day 6. This prompted us to use pharmacokinetic (PK) and parametric time-to-event (TTE) modeling to simulate dosage schedules that may decrease the time to stabilization and reduce the need for adjunct therapy. Population PK (popPK) analysis was conducted, and the final model was a one-compartment model with first-order absorption and elimination, incorporating allometric scaling and age effect on apparent clearance (CL/F) and apparent volume (V/F). The population estimates for CL/F and V/F were 13.6 L/h/70 kg and 416 L/70 kg, respectively, similar to the reported values. A Weibull model described the TTE data best, followed by incorporating predicted average concentrations to yield the final Weibull accelerated failure time model. Simulations of dosing strategies showed that increasing both the starting and maximum doses could potentially shorten the time to stabilization, and thus, length of treatment and hospital stay. Given the hypothesis-generating nature of this analysis, the recommended dosing regimens should be tested prospectively to evaluate their benefits.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685578","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":"Mechanistic Modeling of Spatial Heterogeneity of Drug Penetration and Exposure in the Human Central Nervous System and Brain Tumors.","authors":"Jing Li, Charuka Wickramasinghe, Jun Jiang, Andrew Wu, Yuanyuan Jiang, Artak Tovmasyan, Seongho Kim, Nader Sanai","doi":"10.1002/cpt.3505","DOIUrl":"https://doi.org/10.1002/cpt.3505","url":null,"abstract":"<p><p>Direct measurement of spatial-temporal drug penetration and exposure in the human central nervous system (CNS) and brain tumors is difficult or infeasible. This study aimed to develop an innovative mechanistic modeling platform for quantitative prediction of spatial pharmacokinetics of systemically administered drugs in the human CNS and brain tumors. A nine-compartment CNS (9-CNS) physiologically-based pharmacokinetic model was developed to account for general anatomical structure and pathophysiological heterogeneity of the human CNS and brain tumors. Drug distribution into and within the CNS and tumors is driven by plasma concentration-time profiles and governed by drug properties and CNS pathophysiology. The model was validated by comparisons of model predictions and clinically observed data of six drugs (abemaciclib, ribociclib, pamiparib, olaparib, temuterkib, and ceritinib) in glioblastoma patients. As rigorously validated, the 9-CNS model allows reliable prediction of spatial pharmacokinetics in different regions of the brain parenchyma (i.e., parenchyma adjacent to CSF and deep parenchyma), tumors (i.e., tumor rim, bulk tumor, and tumor core), and CSF (i.e., ventricular CSF, cranial and spinal subarachnoid CSF). By considering inter-individual plasma pharmacokinetic variability and CNS/tumor heterogeneity, the model well predicts the inter-individual variability and spatial heterogeneity of drug exposure in the CNS and tumors as observed for all six drugs in glioblastoma patients. The 9-CNS model is a first-of-its kind, mechanism-based computational modeling platform that enables early reliable prediction of spatial CNS and tumor pharmacokinetics based on plasma concentration-time profiles. It provides a valuable tool to assist rational drug development and treatment for brain cancer.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685577","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":"Planning and Implementing Master Protocol Trials in Japan: Key Considerations of the Japanese Guideline.","authors":"Akihiro Hirakawa, Takashi Asakawa, Kota Tokushige, Ryoto Ozaki, Mizuki Yoshida, Hitomi Sumiyoshi Okuma, Sho Saito, Yosuke Shimizu, Ryo Kitabayashi, Ryoichi Hanazawa, Hiroyuki Sato, Yukari Uemura","doi":"10.1002/cpt.3508","DOIUrl":"https://doi.org/10.1002/cpt.3508","url":null,"abstract":"<p><p>The importance of master protocol trials, which encompass basket, umbrella, and platform trials, has been increasingly recognized worldwide for their efficiency in evaluating multiple drugs or diseases within a single trial. While the US Food and Drug Administration and European regulatory bodies have issued guidelines to facilitate such trials, Japan only recently introduced its own set of guidelines to address the unique challenges and opportunities within its regulatory and healthcare landscape. Our study elaborates on these newly issued Japanese guidelines, which were developed through a collaborative effort involving biostatisticians, physicians, clinical trialists, regulatory authorities, and industry representatives. We provide a comprehensive overview of the guidelines, emphasizing their structure, content, and key considerations for effective planning and implementation. By highlighting the specific adaptations and innovations required to conduct master protocol trials in Japan, we aim to contribute to the broader discourse on optimizing clinical trial frameworks and enhancing drug development efficiency.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685579","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":"Contemporary Use of β-Blockers in Heart Failure Patients With and Without Atrial Fibrillation: A Nationwide Database Analysis.","authors":"Michikazu Nakai, Yoshitaka Iwanaga, Koshiro Kanaoka, Yoko Sumita, Yuichi Nishioka, Tomoya Myojin, Katsuki Okada, Tatsuya Noda, Tomoaki Imamura, Yoshihiro Miyamoto","doi":"10.1002/cpt.3496","DOIUrl":"https://doi.org/10.1002/cpt.3496","url":null,"abstract":"<p><p>Evidence of the effectiveness of β-blockers in heart failure (HF) and atrial fibrillation (AF) in a contemporary cohort is controversial. This study investigated the association between the use of β-blockers and prognosis in hospitalized HF patients with and without AF in Japan. Patients hospitalized with the first episode of acute HF were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan between April 2014 and March 2021. Associations of β-blocker use and prognosis were compared by propensity score matching among the AF or non-AF group. A mixed-effects survival model was used, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Among 428,650 patients discharged with HF in 4,433 hospitals, 175,174 (40.9%) were ≥ 85 years old, 151,873 (35.4%) had complicated AF, and 236,457 (55.2%) were β-blocker users. In a matched AF group, β-blocker use was associated with a lower composite outcome of all-cause mortality or HF rehospitalization (HR [95% CI], 0.95 [0.93-0.97]). A similar result was obtained in a matched non-AF group (0.95 [0.94-0.96]). In addition, the HRs in patients aged ≥ 85 years and female patients were 1.00 [0.98-1.02] and 1.01 [0.98-1.03] in the AF group and 1.03 [1.01-1.05] and 0.98 [0.97-1.00] in the non-AF group, respectively. The favorable prognostic associations of β-blocker use were observed regardless of AF in patients across a broad spectrum of HF in a superaged society.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646231","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":"Correction to Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions","authors":"","doi":"10.1002/cpt.3453","DOIUrl":"10.1002/cpt.3453","url":null,"abstract":"<p>Sola-Morales, O. <i>et al</i>. Effectively leveraging RWD for external controls: a systematic literature review of regulatory and HTA decisions. <i>Clin. Pharmacol. Ther</i>. <b>114</b>, 325–355 (2023). https://doi.org/10.1002/cpt.2914</p><p>The following adjustments should be made to the text:\u0000 </p><p>\u0000 <b>References</b>\u0000 </p><p>124. NICE. Asfotase alfa for treating paediatric-onset hypophosphatasia &lt;https://www.nice.org.uk/guidance/hst6&gt; (2017). Accessed 24 May, 2024.</p><p>125. NICE. Onasemnogene abeparvovec for treating spinal muscular atrophy https://www.nice.org.uk/guidance/hst15 (2021). Accessed 24 May, 2024.</p><p>126. GBA. Certinib. Supporting Grounds &lt;https://www.g-ba.de/downloads/40-268-3496/2015-12-17_AM-RL-XII_Ceritinib_2015-07-01-D-171_TrG.pdf&gt; (2015). Accessed 24 May, 2024.</p><p>127. GBA. Efmoroctocog alfa. Supporting Grounds &lt;https://www.g-ba.de/downloads/40-268-3824/2016-06-16_AM-RL-XII_Efmoroctocog-alfa_D-195_TrG.pdf&gt; (2016). Accessed 24 May, 2024.</p><p>128. GBA. Nivolumab. Supporting Grounds &lt;https://www.g-ba.de/downloads/40-268-4426/2017-06-15_AM-RL-XII_Nivolumab_D-267_TrG.pdf&gt; (2017). Accessed 12 August, 2024.</p><p>129. NICE. Vismodegib for treating basal cell carcinoma &lt;https://www.nice.org.uk/guidance/ta489&gt; (2017). Accessed 24 May, 2024.</p><p>We hope that these updates improve the interpretation and clarity of this manuscript.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 1","pages":"289-308"},"PeriodicalIF":6.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3453","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637963","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":"HIGHLIGHTED ARTICLES","authors":"","doi":"10.1002/cpt.3476","DOIUrl":"https://doi.org/10.1002/cpt.3476","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"116 6","pages":"1369-1370"},"PeriodicalIF":6.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142664806","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":"Therapeutic Orphan No More: Role for Clinical Pharmacology and Translational Science in Developing Therapeutics for Rare and Neglected Diseases","authors":"Anuradha Ramamoorthy,&nbsp;Islam Younis,&nbsp;Ya-Feng Wen,&nbsp;Mai Mehanna,&nbsp;Kathleen M. Giacomini,&nbsp;Piet H. van der Graaf","doi":"10.1002/cpt.3474","DOIUrl":"10.1002/cpt.3474","url":null,"abstract":"&lt;p&gt;Rare disease (a disease that affects fewer than 1 in about 2,000 people&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;) and neglected disease (an infectious disease that is present in lower income countries) have very limited therapeutic options and can be considered as “therapeutic orphans.” Collectively, rare and neglected diseases are estimated to affect nearly 2 billion people worldwide – about 300 million people are estimated to be affected by rare diseases and 1.7 billion by neglected tropical diseases.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; However, it is reported that only &lt;5% of rare diseases and a limited number of neglected diseases have therapeutic options available.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; That is, even though one in four people globally are affected by these diseases, very limited therapeutic options exist for these patients. In this special issue, we focus on rare diseases to highlight challenges and opportunities in developing therapies for these diseases and showcase the current and future role of clinical pharmacology and translational sciences in addressing the challenges and taking advantage of the opportunities. Additionally, the American Society for Clinical Pharmacology &amp; Therapeutics (ASCPT) 2024 Annual Meeting Award and State-of-Art lectures summarized in this issue also highlight the challenges and opportunities in developing effective therapies for the neglected diseases (e.g., tropical diseases including tuberculosis) and neglected populations (e.g., pregnant women or breastfeeding mothers). Our intention for this special issue of &lt;i&gt;Clinical Pharmacology &amp; Therapeutics&lt;/i&gt; (&lt;i&gt;CPT&lt;/i&gt;) is that we can all collectively learn from these examples and experiences to accelerate drug development for these therapeutic orphans (&lt;b&gt;Figure&lt;/b&gt; 1).&lt;/p&gt;&lt;p&gt;There are a number of challenges in developing therapies for rare diseases. Because each rare disease afflicts only a small number of patients, the market size is relatively limited, and consequently, developing drugs for many of these diseases may not be considered as being commercially attractive. Additionally, most rare diseases are poorly understood because limited longitudinal natural history data are available, and consequently, more information on disease etiology, pathogenesis, genotype-to-phenotype correlation, disease progression, and outcome is needed. Furthermore, the small patient population size can lead to difficulties in enrolling sufficient numbers of patients in clinical trials and in generating adequate data to determine the benefit–risk profile of the drug. Compounding these challenges, there may be a lack of well-established biomarkers or animal models that can be leveraged during drug development. In sum, insufficient commercial interest and inadequate scientific research make it challenging to develop effective therapeutics for rare diseases.&lt;/p&gt;&lt;p&gt;Recognizing some of these challenges and limitations, several regulatory agencies and public-private partnerships have focuse","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"116 6","pages":"1363-1368"},"PeriodicalIF":6.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3474","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612878","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":"A Systematic Review of the Costs of Drug-Associated Acute Kidney Injury and Potential Cost Savings with Nephrotoxin Stewardship Prevention Strategies.","authors":"Britney A Stottlemyer, Tiffany Tran, Kangho Suh, Sandra L Kane-Gill","doi":"10.1002/cpt.3493","DOIUrl":"https://doi.org/10.1002/cpt.3493","url":null,"abstract":"<p><p>There is a scarcity of information related to the financial impact of acute kidney injury (AKI), and even more so the economics of drug-associated AKI (D-AKI). Our goal was to provide a comprehensive summary of the economic burden of D-AKI by evaluating the costs of D-AKI compared to not developing AKI and cost savings associated with nephrotoxin stewardship approaches. Following the PRISMA guidelines, a literature search was conducted using PubMed to identify articles from database inception through November 2023. The main outcomes included AKI incidence, resource use, and cost of nephrotoxin stewardship programs/D-AKI event or no event. Key findings were summarized based on whether the study compared the cost of D-AKI vs. no AKI or identified potential cost savings associated with a nephrotoxin stewardship method to prevent D-AKI or worsening D-AKI. All costs were adjusted to USD2023. Twenty-five studies met the inclusion criteria. Eight studies compared the cost of D-AKI to no AKI. Total admission costs of patients who developed D-AKI ranged from $47,696 to $173,569. Nineteen studies implemented nephrotoxin stewardship with 12 substituting a less nephrotoxic drug; five using therapeutic drug monitoring and two altering drug dosing to limit exposure. Overall, these prevention strategies ranged from $5,171 to $364,973 in total medical cost savings and $17 to $942 in total cost savings per patient-day. The in-hospital economic impact of D-AKI is substantial. Implementing nephrotoxin stewardship strategies to reduce D-AKI is associated with cost savings. Institutions should adopt strategic and efficient nephrotoxin stewardship programs to optimize patient care and reduce costs.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612719","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":"Narrow Therapeutic Index Drugs: FDA Experience, Views, and Operations","authors":"Mark Donnelly,&nbsp;Lanyan Fang,&nbsp;Rajanikanth Madabushi,&nbsp;Hao Zhu,&nbsp;Markham Luke,&nbsp;Crystal Canterbury,&nbsp;Bruce Lerman,&nbsp;Paramjeet Kaur,&nbsp;Devvrat Patel,&nbsp;Wanjie Sun,&nbsp;Don Schuirmann,&nbsp;Steven Dinsmore,&nbsp;Mehul Mehta,&nbsp;Liang Zhao","doi":"10.1002/cpt.3460","DOIUrl":"10.1002/cpt.3460","url":null,"abstract":"<p>The U.S. Food and Drug Administration (FDA) has defined narrow therapeutic index (NTI) drugs as “those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity.” FDA has undertaken efforts to develop NTI assessment criteria and enhance public confidence in generic NTI drugs through public workshops, research, and post-marketing surveillance. In 2015, FDA formed the NTI Drug Working Group to develop a consistent approach to identify NTI drugs and resolve NTI-related scientific and regulatory issues in a transparent and collaborative manner. One key objective of the NTI Drug Working Group is to evaluate potential NTI drugs based on five general characteristics of NTI drugs as highlighted in the case example for theophylline drug products. As of January 5, 2024, there are 33 drug products, with 14 distinct active ingredients, specified as NTI drugs in their respective product-specific guidances (PSGs) for generic drug development. Future collaborative efforts with other agencies to harmonize the terms and definitions for NTI drugs may help enhance clarity and consistency during the drug development and the regulatory review process.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 1","pages":"116-129"},"PeriodicalIF":6.3,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3460","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612862","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}