Clinical Pharmacology & Therapeutics最新文献

{"title":"A Phase I Trial of the Pharmacokinetic Interaction Between Cannabidiol and Tacrolimus.","authors":"Gerald C So, Jessica Bo Li Lu, Sachiko Koyama, Ying-Hua Cheng, Debora L Gisch, Kelsey McClara, Paul R Dexter, Asif A Sharfuddin, Jumar Etkins, Emma M Tillman, Travis R Beamon, Zachary Cowsert, Jennifer S Stuart, Zeruesenay Desta, Michael T Eadon","doi":"10.1002/cpt.3504","DOIUrl":"https://doi.org/10.1002/cpt.3504","url":null,"abstract":"<p><p>One in six Americans uses cannabidiol-based or cannabis-derived products. Cannabidiol is a substrate of CYP3A, but its role as a potential CYP3A inhibitor remains unclear. We hypothesized that cannabidiol would inhibit CYP3A-mediated metabolism of tacrolimus. This report is an interim analysis of an open-label, three-period, fixed-sequence, crossover study in healthy participants. Participants first received a single dose of tacrolimus 5 mg orally. After washout, participants later received cannabidiol titrated to 5 mg/kg twice daily for 14 days to reach a steady state, followed by a second single dose of tacrolimus 5 mg orally. Tacrolimus concentrations in whole blood were measured by UHPLC-MS/MS method. Pharmacokinetic parameters were calculated by noncompartmental analysis. Twelve participants completed all periods of the study. The maximum concentration (C_max) of tacrolimus increased 4.2-fold (P < 0.0001) with cannabidiol (40.2 ± 13.5 ng/mL) compared with without cannabidiol (9.85 ± 4.63 ng/mL). The area under the concentration-vs.-time curve (AUC_0-∞) increased 3.1-fold (P < 0.0001). No change in half-life (t_1/2) was observed. This study demonstrates that cannabidiol increases tacrolimus exposure. Our data suggest the need for dose reduction in tacrolimus and frequent therapeutic dose monitoring in transplant patients taking cannabidiol concomitantly. Whether this observed interaction occurred due to the inhibition of CYP3A4 and/or CYP3A5 in the liver, intestine, or both, or intestinal drug transporters (e.g., p-glycoprotein) during the first-pass elimination remains to be elucidated.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724538","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":"Oxygenation Effects of Antihypertensive Agents in Intensive Care: A Prospective Comparative Study of Nicardipine and Urapidil.","authors":"Florimond Suard, Martin Mombrun, Marc-Olivier Fischer, Jean-Luc Hanouz, Jean-Baptiste Decros, Sébastien Derville, Clément Gakuba, Gulbhar Al Issa, Caroline Menard, Basile Chretien, Richard Descamps","doi":"10.1002/cpt.3509","DOIUrl":"https://doi.org/10.1002/cpt.3509","url":null,"abstract":"<p><p>Acute arterial hypertension within the critical care context may necessitate the administration of intravenous antihypertensive agents. Nicardipine and urapidil are notable for their application in intensive care units. Nonetheless, dihydropyridine calcium channel inhibitors (DCCIs) such as nicardipine are implicated in the impairment of hypoxic pulmonary vasoconstriction, potentially disrupting oxygenation. This study aimed to assess the differences in patient oxygenation when these antihypertensive agents are administered intravenously. This bicentric, prospective, observational investigation spanning five intensive care units evaluated patients requiring intravenous nicardipine or urapidil. Oxygenation data were recorded from the start of therapy until the 12th hour. Comparative analysis was performed between patient groups based on the antihypertensive agent administered, along with subgroup investigations to identify populations with an elevated risk of hypoxemia. From November 2021 to November 2023, 197 patients were included: 98 (50%) were treated with nicardipine, and 99 (50%) were treated with urapidil. Hypoxemia occurred in 97 (49%) patients and was more prevalent in the nicardipine cohort, affecting 65 (66%) patients, as opposed to 32 (32%) patients in the urapidil cohort (RR 2.05, 95% CI [1.48-2.82], P < 0.001). Subgroup analysis revealed a significant association between patients with pulmonary atelectasis (RR 2.30, 95% CI [1.4-3.7], P < 0.001) and obesity (RR 2.7, 95% CI [1.5-4.6], P < 0.001). Considering these findings, cautious consideration of the patient's respiratory status should be exercised when initiating intravenous DCCI treatment. However, given the limitations of this study, a controlled trial on hypertension management in the ICU is needed.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737845","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, Jean-Christophe Boyer, Claire Lafay-Chebassier, Benjamin Hennart, Sarah Baklouti, Séverine Cunat, Paul Vilquin, Yves Medard, Elodie Gautier-Veyret, Clara Laffitte-Redondo, Céline Verstuyft, Abd El Kader Ait Tayeb, Vincent Haufroid, Julien Wils, Fabien Lamoureux, Alexandre Evrard, Julie Davaze-Schneider, Mouna Ben-Sassi, Nicolas Picard, Sylvie Quaranta, Estelle Ayme-Dietrich","doi":"10.1002/cpt.3502","DOIUrl":"https://doi.org/10.1002/cpt.3502","url":null,"abstract":"<p><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 CYP2C19 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 CYP2C19 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 CYP2C19 and CYP3A4/CYP3A5 genotype.</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":"142708761","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":"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":"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":"https://doi.org/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":"https://doi.org/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, Peter Arlett, Kit Roes, Flora Musuamba Tshinanu, Gabriel Westman, Zaide Frias, Hilmar Hamann, Joaquim Berenguer Jornet, Iftekhar Khan, Jeppe Larsen, Karl Broich, Emer Cooke","doi":"10.1002/cpt.3494","DOIUrl":"https://doi.org/10.1002/cpt.3494","url":null,"abstract":"","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":"142685576","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}