Clinical Pharmacology & Therapeutics最新文献

{"title":"Clinical and Physiologically Based Pharmacokinetic Model Evaluations of Adagrasib Drug-Drug Interactions.","authors":"Cornelius Cilliers, Eleanor Howgate, Hannah M Jones, Lisa Rahbaek, Jonathan Q Tran","doi":"10.1002/cpt.3506","DOIUrl":"https://doi.org/10.1002/cpt.3506","url":null,"abstract":"<p><p>Adagrasib is a potent, highly selective, orally available, small molecule, covalent inhibitor of G12C mutated KRAS. As both a substrate and strong inhibitor of cytochrome P450 (CYP) 3A4, adagrasib inhibits its own CYP3A4-mediated metabolism following multiple dosing, resulting in time-dependent drug-drug interaction (DDI) liabilities. A physiologically-based pharmacokinetic (PBPK) model was developed and verified using a combination of physicochemical, in vitro and clinical pharmacokinetic (PK) data from healthy volunteers and cancer patients. The PBPK model well-described the single and multiple-dose adagrasib PK data as well as DDI data with itraconazole, rifampin, midazolam, warfarin, dextromethorphan, and digoxin, with model predictions within 1.5-fold of the observed clinical data. The PBPK model was used to predict untested scenarios including the clinical victim and perpetrator DDI liabilities at the approved dosing regimen of 600 mg twice daily (b.i.d.) in cancer patients. Strong, moderate, and weak inhibitors of CYP3A4 are predicted to have a negligible effect on the steady-state exposure of adagrasib 600 mg b.i.d. resulting from the significant inactivation of CYP3A4 by adagrasib. Additionally, strong and moderate inducers of CYP3A4 are predicted to decrease adagrasib exposure by 68% and 22%, respectively. As a perpetrator, adagrasib 600 mg b.i.d. is predicted to be a strong inhibitor of CYP3A4, a moderate inhibitor of CYP2C9 and CYP2D6, and an inhibitor of P-glycoprotein (P-gp). These results successfully supported regulatory interactions with the United States Food and Drug Administration regarding dosing recommendations for when adagrasib is used concomitantly with other medications, supporting a range of label claims in lieu of clinical trials.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714980","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":"French-Speaking Network of Pharmacogenetics (RNPGx) Recommendations for Clinical Use of Mavacamten","authors":"Louis Lebreton,&nbsp;Jean-Christophe Boyer,&nbsp;Claire Lafay-Chebassier,&nbsp;Benjamin Hennart,&nbsp;Sarah Baklouti,&nbsp;Séverine Cunat,&nbsp;Paul Vilquin,&nbsp;Yves Medard,&nbsp;Elodie Gautier-Veyret,&nbsp;Clara Laffitte-Redondo,&nbsp;Céline Verstuyft,&nbsp;Abd El Kader Ait Tayeb,&nbsp;Vincent Haufroid,&nbsp;Julien Wils,&nbsp;Fabien Lamoureux,&nbsp;Alexandre Evrard,&nbsp;Julie Davaze-Schneider,&nbsp;Mouna Ben-Sassi,&nbsp;Nicolas Picard,&nbsp;Sylvie Quaranta,&nbsp;Estelle Ayme-Dietrich,&nbsp;the French-Speaking Network of Pharmacogenetics (RNPGx)","doi":"10.1002/cpt.3502","DOIUrl":"10.1002/cpt.3502","url":null,"abstract":"<p>Mavacamten, the first drug in the class of β-cardiac myosin modulator, is used for the treatment of patients with hypertrophic cardiomyopathy. This orally administered drug demonstrates wide interpatient variability in pharmacokinetics parameters, due in part to variant <i>CYP2C19</i> alleles. Individuals who are CYP2C19 poor metabolizers have increased exposure and are at increased risk of reduced cardiac hypercontractility. To ensure the safety of all patients, European Medicines Agency recommends <i>CYP2C19</i> preemptive genotyping, and consecutively, to adapt maintenance and initial mavacamten doses, and to manage drug–drug interactions, according to CYP2C19 phenotype. In this article, we summarize evidence from the literature supporting the association between CYP2C19 phenotype and pharmacological features of mavacamten and provide, beyond biologic guidelines, therapeutic recommendations for the use of mavacamten based on <i>CYP2C19</i> and <i>CYP3A4/CYP3A5</i> genotype.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 2","pages":"387-397"},"PeriodicalIF":6.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708761","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":"Discovering Severe Adverse Reactions From Pharmacokinetic Drug-Drug Interactions Through Literature Analysis and Electronic Health Record Verification.","authors":"Eugene Jeong, Yu Su, Lang Li, You Chen","doi":"10.1002/cpt.3500","DOIUrl":"10.1002/cpt.3500","url":null,"abstract":"<p><p>While drug-drug interactions (DDIs) and their pharmacokinetic (PK) mechanisms are well-studied prior to drug approval, severe adverse drug reactions (SADRs) caused by DDIs often remain underrecognized due to limitations in pre-marketing clinical trials. To address this gap, our study utilized a literature database, applied natural language processing (NLP) techniques, and conducted multi-source electronic health record (EHR) validation to uncover underrecognized DDI-SADR signals that warrant further investigation. PubMed abstracts related to DDIs from January 1962 to December 2023 were retrieved. We utilized PubTator Central for Named Entity Recognition (NER) to identify drugs and SADRs and employed SciFive for Relation Extraction (RE) to extract DDI-SADR signals. The extracted signals were cross-referenced with the DrugBank database and validated using logistic regression, considering risk factors including patient demographics, drug usage, and comorbidities, based on EHRs from Vanderbilt University Medical Center (VUMC) and the All of Us research program. From 160,321 abstracts, we identified 111 DDI-SADR signals. Seventeen were statistically significant (13 by one EHR and 4 by both EHR databases), with 9 being previously not recorded in the DrugBank. These included methadone-ciprofloxacin-respiratory depression, oxycodone-fluvoxamine-clonus, tramadol-fluconazole-hallucination, simvastatin-fluconazole-rhabdomyolysis, ibrutinib-amiodarone-atrial fibrillation, fentanyl-diltiazem-delirium, clarithromycin-voriconazole-acute kidney injury, colchicine-cyclosporine-rhabdomyolysis, and methadone-voriconazole-arrhythmia (odds ratios (ORs) ranged from 1.9 to 35.83, with P-values ranging from < 0.001 to 0.017). Utilizing NLP to extract DDI-SADRs from Biomedical Literature and validating these findings through multiple-source EHRs represents a pioneering approach in pharmacovigilance. This method uncovers clinically relevant SADRs resulting from DDIs that were not evident in pre-marketing trials or the existing DDI knowledge base.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708759","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":"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":"Artificial Intelligence in European Medicines Regulation: From Vision to Action. Harnessing the Capabilities of Artificial Intelligence for the Benefit of Public and Animal Health","authors":"Luis Correia Pinheiro,&nbsp;Peter Arlett,&nbsp;Kit Roes,&nbsp;Flora Musuamba Tshinanu,&nbsp;Gabriel Westman,&nbsp;Zaide Frias,&nbsp;Hilmar Hamann,&nbsp;Joaquim Berenguer Jornet,&nbsp;Iftekhar Khan,&nbsp;Jeppe Larsen,&nbsp;Karl Broich,&nbsp;Emer Cooke","doi":"10.1002/cpt.3494","DOIUrl":"10.1002/cpt.3494","url":null,"abstract":"&lt;p&gt;The paper “Artificial intelligence in European medicines regulation” (Nature Reviews Drug Discovery, 2022),&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; presented the European Medicines Agency's (EMA) perspective on artificial intelligence (AI). The paper detailed an approach to working together with stakeholders to deliver a roadmap on AI for the benefit of public and animal health.&lt;/p&gt;&lt;p&gt;Through the joint Heads of Medicines Agency (HMA) and EMA Big Data Steering Group (BDSG),&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; the European Medicines Regulatory Network (EMRN) has since made rapid progress.&lt;/p&gt;&lt;p&gt;Here, we set out the vision and areas of focus, and how they translate into a multi-annual workplan aimed at enabling the safe and responsible use of AI in the medicines lifecycle for the benefit of public and animal health.&lt;/p&gt;&lt;p&gt;There are three areas of focus for the EMRN's AI transformation: the ability to regulate products that include AI in their lifecycle as required, the ability to leverage AI for process improvement and analytics, and the ability to leverage AI for advanced healthcare data analytics. These focus areas underpin the EMRN's vision for AI: “a regulatory system harnessing the capabilities of AI for personal productivity, process automation and systems efficiency, increased insights into data and strengthened decision-support for the benefit of public and animal health.”&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In November 2023, the EMRN held a public workshop&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; to hear the views of stakeholders on a draft reflection paper on the use of AI in the medicines lifecycle,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; on a vision for AI in medicines regulation and on a draft plan of actions to deliver that vision. With the perspectives of stakeholders shared, in December 2023 the first EMRN multi-annual AI workplan was published.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The workplan includes four interconnected streams. “Guidance, policy, and product support” will ensure there is support to product development and submissions through advice to biopharmaceutical companies and through guidance on AI, and that the EMRN adapts quickly to the evolving AI legal framework. “Tools and technology” will ensure robust technology is available to the EMRN to enable the deployment of AI-powered applications in full compliance with EU data protection requirements. “Collaboration and change management” will ensure the input of stakeholders at European and international levels is leveraged, and EMRN staff is empowered with the knowledge and skills needed to realize the benefits and manage the risks of AI. Through fostering a culture of continuous learning and adaptation, the EU Network Training Centre (EU NTC) endeavors to cultivate a dynamic learning ecosystem that thrives on innovation, inclusivity, and sustainability in a rapidly evolving landscape of AI. With respect to “Experimentation,” the EMRN aims to create an environment that can explore AI's potential while mitigating risks related to privac","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 2","pages":"335-336"},"PeriodicalIF":6.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685576","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":"Cerebral Ischemia Protection After Aneurysmal Subarachnoid Hemorrhage: CSF Nimodipine Levels After Intravenous Versus Oral Nimodipine Administration","authors":"Miriam M. Moser,&nbsp;Karl Rössler,&nbsp;Dorian Hirschmann,&nbsp;Leon Gramss,&nbsp;Ammar Tahir,&nbsp;Walter Plöchl,&nbsp;Johannes Herta,&nbsp;Andrea Reinprecht,&nbsp;Markus Zeitlinger,&nbsp;Arthur Hosmann","doi":"10.1002/cpt.3499","DOIUrl":"10.1002/cpt.3499","url":null,"abstract":"<p>There is accumulating evidence that cerebrospinal fluid (CSF) concentrations of nimodipine correlate with long-term outcome of patients after subarachnoidal hemorrhage (aSAH) by impeding cerebral ischemia. However, pharmacological data on simultaneous serum vs. CSF and intraparenchymal nimodipine values are rarely reported in larger patient groups. Nimodipine concentrations were determined in plasma, CSF, and cerebral interstitial fluid (ISF), at steady state after oral (6 × 60 mg/day) and intravenous (0.5, 1, 1.5 and 2 mg/h) administrations in 10 patients after aSAH. Area under the concentration time curve (AUC_0–24) for intravenous nimodipine was highest at an infusion rate of 2 mg/h in plasma (1335.87 ± 591.09 mg*h/L), followed by CSF (39.53 ± 23.07 mg*h/L), resulting in an overall CSF penetration ratio of 3.8% (±1.5) (AUC_CSF/AUC_plasma). In contrast, nimodipine levels were significantly lower in both plasma (AUC_0–24 298.32 ± 206.52 mg*h/L) and CSF (AUC_0–24 34.8 ± 16.56 mg*h/L) after oral administration. In cerebral ISF, low amounts of nimodipine were detectable in only 4 patients at an infusion rate of 1.5 and 2 mg/h as well as following oral administration. We found significantly higher CSF nimodipine levels in patients during intravenous compared to oral administration. In contrast, only low amounts of nimodipine were detected in the ISF after both oral and intravenous administration. Our findings strongly suggest that the main clinical nimodipine effect of impeding life threatening cerebral ischemia is mediated through significant higher CSF levels after intravenous administration, more likely effective than oral administration.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 2","pages":"589-597"},"PeriodicalIF":6.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666548","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":"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}