Clinical Pharmacology & Therapeutics最新文献_第2页

The Potential of Disease Progression Modeling to Advance Clinical Development and Decision Making. 疾病进展模型推进临床开发和决策的潜力。

IF 6.3 2区医学

Clinical Pharmacology & Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-10-15 DOI: 10.1002/cpt.3467

Mary Summer Starling, Lindsay Kehoe, Bruce K Burnett, Phil Green, Karthik Venkatakrishnan, Rajanikanth Madabushi

{"title":"The Potential of Disease Progression Modeling to Advance Clinical Development and Decision Making.","authors":"Mary Summer Starling, Lindsay Kehoe, Bruce K Burnett, Phil Green, Karthik Venkatakrishnan, Rajanikanth Madabushi","doi":"10.1002/cpt.3467","DOIUrl":"10.1002/cpt.3467","url":null,"abstract":"While some model-informed drug development frameworks are well recognized as enabling clinical trials, the value of disease progression modeling (DPM) in impacting medical product development has yet to be fully realized. The Clinical Trials Transformation Initiative assembled a diverse project team from across the patient, academic, regulatory, and industry sectors of practice to advance the use of DPM for decision making in clinical trials and medical product development. This team conducted a scoping review to explore current applications of DPM and convened a multi-stakeholder expert meeting to discuss its value in medical product development. In this article, we present the scoping review and expert meeting output and propose key questions that medical product developers and regulators may use to inform clinical development strategy, appreciate the therapeutic context and endpoint selection, and optimize trial design with disease progression models. By expanding awareness of the unique value of DPM, this article does not aim to be technical in nature but rather aims to highlight the potential of DPM to improve the quality and efficiency of medical product development.","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"343-352"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454183","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}

引用次数: 0

Concordance Between Pharmaceuticals and Medical Devices Agency Review and Ministry of Health, Labour and Welfare Decision Among New Drug Applications in Japan. 日本新药申请中药品和医疗器械机构审查与厚生劳动省决定的一致性。

IF 6.3 2区医学

Clinical Pharmacology & Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-11-08 DOI: 10.1002/cpt.3485

Makoto Miyazawa, Mototsugu Tanaka, Yusuke Tanaka, Ryohei Terashima, Mio Ezura, Haruna Miyazawa, Mutsuhiro Ikuma, Yoshihiko Tomita

{"title":"Concordance Between Pharmaceuticals and Medical Devices Agency Review and Ministry of Health, Labour and Welfare Decision Among New Drug Applications in Japan.","authors":"Makoto Miyazawa, Mototsugu Tanaka, Yusuke Tanaka, Ryohei Terashima, Mio Ezura, Haruna Miyazawa, Mutsuhiro Ikuma, Yoshihiko Tomita","doi":"10.1002/cpt.3485","DOIUrl":"10.1002/cpt.3485","url":null,"abstract":"New drug applications (NDAs) in Japan are reviewed by the Pharmaceuticals and Medical Devices Agency (PMDA). Those that pass the review are subsequently subject to deliberation by the Ministry of Health, Labour and Welfare Pharmaceutical Affairs and Food Sanitation Councils (MHLW-PAFSC), and the MHLW legislatively grants approval based on its positive opinions. However, little is known regarding the relationship between the PMDA review and the MHLW decision. We retrospectively assessed the MHLW decision of NDAs that passed the PMDA review at the initial MHLW-PAFSC deliberation from 2002 to 2022. The reasoning behind a non-supportive opinion from the MHLW-PAFSC and the sponsor's actions to overcome unresolved issues were also documented. A total of 2,117 of 2,153 (98.3%) NDAs that passed the PMDA review were approved at the initial MHLW-PAFSC deliberation with a positive opinion. The remaining 36 applications were not approved at the initial deliberation and subjected to continued deliberation because of a non-supportive opinion from the councils, although 29 were finally approved through revision of the application document (24 applications), re-analysis of the data (1 application), or additional clinical trials (4 applications). Seven applications have not been approved, of which one was refused, four were withdrawn, and two were unknown. The MHLW approves NDAs that passed the PMDA review at the initial deliberation at a high rate, suggesting that NDAs only suitable for approval passed the review and reached the MHLW-PAFSC deliberation. Only a few NDAs were not approved at the initial deliberation; however, most of them were finally approved.","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"544-553"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602396","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}

引用次数: 0

The Impact of QT-Prolonging Medications and Drug-Drug Interactions on QTc Interval Prolongation in Hospitalized Patients: A Case-Crossover Study. QT 延长药物和药物间相互作用对住院患者 QTc 间期延长的影响：病例交叉研究

IF 6.3 2区医学

Clinical Pharmacology & Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-10-09 DOI: 10.1002/cpt.3469

Hsiu-Ting Chien, Fang-Ju Lin, Jyh-Ming Jimmy Juang, Shu-Wen Lin

{"title":"The Impact of QT-Prolonging Medications and Drug-Drug Interactions on QTc Interval Prolongation in Hospitalized Patients: A Case-Crossover Study.","authors":"Hsiu-Ting Chien, Fang-Ju Lin, Jyh-Ming Jimmy Juang, Shu-Wen Lin","doi":"10.1002/cpt.3469","DOIUrl":"10.1002/cpt.3469","url":null,"abstract":"Researchers have studied potential corrected QT interval (QTc) prolongation from drug-drug interactions (DDIs), raising unresolved questions about their real-world impact. This retrospective case-crossover study investigated the effects of QT-prolonging drugs and DDIs on QTc prolongation in hospitalized patients aged 45 years and above. The cohort comprised patients who had multiple hospitalizations and developed QTc prolongation (QTc > 500 ms or an increase of >60 ms from baseline) at least 24 hours after admission between 2011 and 2019. Conditional logistic regression compared drug exposure between hospitalizations with QTc prolongation (case window) and those without (reference window). Among 2,276 patients (mean age 71; 43.8% female), the use of QT-prolonging drugs significantly increased the risk of QTc prolongation (odds ratio: 2.42 (95% confidence interval: 1.95-3.02)). The risk was higher with drugs of \"known risks\" (OR: 3.78 (2.91-4.90)) and \"conditional risk\" (OR: 2.08 (1.65-2.62)). DDIs, particularly involving multiple \"known risk\" drugs (OR: 7.86 (4.96-12.45)), strong cytochrome P450 enzyme inhibitors (OR: 5.57 (2.75-11.30)), or the concurrent use of ≥4 QT-prolonging drugs with any risk (OR: 5.28 (3.96-7.03)) substantially increased the risk. Cautious prescribing for patients with multiple risk factors is important to minimize the likelihood of QTc prolongation. However, when considering enhanced monitoring or drug choices, it is crucial to carefully evaluate the overall risk of QT prolongation against the benefits of treatment to ensure optimal patient care.","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"495-505"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386720","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}

引用次数: 0

An IQ Industry Perspective on Informing Dosing Recommendations in Patients With Renal Impairment. 从智商行业的角度看肾功能受损患者的用药建议。

IF 6.3 2区医学

Clinical Pharmacology & Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-10-22 DOI: 10.1002/cpt.3463

Ashish Sharma, Islam R Younis, Jitendra Kanodia, Vaishali Sahasrabudhe

引用次数: 0

The Impact of Dexamethasone and Prednisone on Apixaban and Rivaroxaban Exposure in COVID-19 Patients: A Physiologically Based Pharmacokinetic Modeling Study. 地塞米松和泼尼松对 COVID-19 患者阿哌沙班和利伐沙班暴露的影响：基于生理学的药代动力学模型研究。

IF 6.3 2区医学

Clinical Pharmacology & Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-11-13 DOI: 10.1002/cpt.3491

Jean Terrier, Kenza Abouir, Frederic Gaspar, Youssef Daali, Caroline Flora Samer

{"title":"The Impact of Dexamethasone and Prednisone on Apixaban and Rivaroxaban Exposure in COVID-19 Patients: A Physiologically Based Pharmacokinetic Modeling Study.","authors":"Jean Terrier, Kenza Abouir, Frederic Gaspar, Youssef Daali, Caroline Flora Samer","doi":"10.1002/cpt.3491","DOIUrl":"10.1002/cpt.3491","url":null,"abstract":"Dexamethasone (DEX) is currently the treatment of choice for patients with oxygen-dependent COVID-19. It has been observed, primarily in vitro, that dexamethasone induces the expression of CYP3A and the ABCB1 gene, which encodes P-glycoprotein (P-gp). This has raised concerns about potential interactions between DEX and substrates of CYP3A and P-gp, such as direct oral anticoagulants (DOAC). Currently, there is limited robust evidence to support a clinically significant interaction between DEX and DOAC. Using physiologically based pharmacokinetic modeling (PBPK), we investigated the impact of DEX administered in the context of SARS-CoV-2 infection on the pharmacokinetics of apixaban (APX) and rivaroxaban (RVX). After validating the induction effect of the DEX compound on two CYP3A4 substrates using the limited available studies, we optimized the compound in a COVID-19 patient population, where significantly higher DEX plasma concentrations were observed compared to healthy volunteers. Our PBPK-based PK simulations showed a 20% decrease in the AUC of APX and RVX in a worst-case scenario and when DEX was administered at 6 mg PO for 10 days. This finding confirms the limited clinical data currently available and supports the use of APX and RVX with DEX in COVID-19 patients at low-risk for thrombo-embolism. In addition, our results suggest that prednisone (PRED), when used at an equipotent dose, could serve as a viable alternative to DEX, given its less pronounced induction effect on APX and RVX. Further research is needed to validate these findings and to explore the clinical implications of using PRED in place of DEX in such scenarios.","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"554-560"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612871","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}

引用次数: 0

Pathway-Based Similarity Measurement to Quantify Transcriptomics Similarity Between Human Tissues and Preclinical Models. 基于通路的相似性测量法量化人体组织与临床前模型之间的转录组学相似性

IF 6.3 2区医学

Clinical Pharmacology & Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-10-08 DOI: 10.1002/cpt.3465

Paarth Parekh, Jason Sherfey, Begum Alaybeyoglu, Murat Cirit

{"title":"Pathway-Based Similarity Measurement to Quantify Transcriptomics Similarity Between Human Tissues and Preclinical Models.","authors":"Paarth Parekh, Jason Sherfey, Begum Alaybeyoglu, Murat Cirit","doi":"10.1002/cpt.3465","DOIUrl":"10.1002/cpt.3465","url":null,"abstract":"Accurate clinical translation of preclinical research remains challenging, primarily due to species-specific differences and disease and patient heterogeneity. An important recent advancement has been development of microphysiological systems that consist of multiple human cell types that recapitulate key characteristics of their respective human systems, allowing essential physiologic processes to be accurately assessed during drug development. However, an unmet need remains regarding a quantitative method to evaluate the similarity between diverse sample types for various contexts of use (CoU)-specific pathways. To address this gap, this study describes the development of pathway-based similarity measurement (PBSM), which leverages RNA-seq data and pathway-based information to assess the human relevance of preclinical models for specific CoU. PBSM offers a quantitative method to compare the transcriptomic similarity of preclinical models to human tissues, shown here as proof of concept for liver and cardiac tissues, enabling improved model selection and validation. Thus, PBSM can successfully support CoU selection for preclinical models, assess the impact of different gene sets on similarity calculations, and differentiate among various in vitro and in vivo models. PBSM has the potential to reduce the translational gap in drug development by allowing quantitative evaluation of the similarity of preclinical models to human tissues, facilitating model selection, and improving understanding of context-specific applications. PBSM can serve as a foundation for enhancing the physiological relevance of in vitro models and supporting the development of more effective therapeutic interventions.","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"485-494"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386718","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}

引用次数: 0

Correction to "Leveraging QSP Models for MIPD: A Case Study for Warfarin/INR". 更正“利用QSP模型进行MIPD：华法林/印度卢比的案例研究”。

IF 6.3 2区医学

Clinical Pharmacology & Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-12-12 DOI: 10.1002/cpt.3517

引用次数: 0

Lenacapavir: Playing the Long Game in the New Era of Antiretrovirals. 来那卡韦在抗逆转录病毒药物的新时代玩转长期游戏

IF 6.3 2区医学

Clinical Pharmacology & Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-09-25 DOI: 10.1002/cpt.3447

Noah C Neverette, Julie B Dumond, Deborah K McMahon, Aaron S Devanathan

{"title":"Lenacapavir: Playing the Long Game in the New Era of Antiretrovirals.","authors":"Noah C Neverette, Julie B Dumond, Deborah K McMahon, Aaron S Devanathan","doi":"10.1002/cpt.3447","DOIUrl":"10.1002/cpt.3447","url":null,"abstract":"The mainstay of antiretroviral therapy (ART) has been combination oral therapy. While oral ART is highly effective, nonadherence remains a chief concern. Addressing this concern in recent years is the emergence of long-acting antiretrovirals for the treatment and prevention of HIV-1 infection. The most recently approved long-acting antiretroviral is the first-in-class capsid inhibitor lenacapavir (LEN) for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Due to its biannual subcutaneous dosing scheme to inhibit the HIV-1 capsid, LEN exhibits unique pharmacokinetics and reinforces an evolving era of ART. In this review, we evaluate published and accepted research articles, conference proceedings, and clinical trial records to provide a comprehensive overview of LEN for treatment and preliminary data for the prevention of HIV-1 infection. These data include clinical trials outcomes, in vitro and in vivo resistance profiles, and preclinical data supporting downstream indications. We also discuss the unique clinical pharmacology of LEN with the goal of serving as a resource toward subsequent physiologically based, population-based, and other miscellaneous pharmacometric-focused analyses. Given the dynamic nature of the HIV treatment and prevention research fields, we also discuss ongoing studies related to LEN for treatment-naïve adults and for prevention. Lastly, we discuss important pharmacologic gaps in special populations, drug-drug interactions, and at the sites of action germane to HIV treatment and prevention. The information discussed in this review will provide knowledge and understanding of the unique pharmacologic properties of LEN to assist clinicians and researchers as they navigate the dynamic HIV research landscape.","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"353-367"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337865","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}

引用次数: 0

Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Studies Related to Vincristine-Induced Peripheral Neuropathy in Chinese Pediatric ALL Patients. 中国小儿 ALL 患者长春新碱诱发周围神经病变的药代动力学、药效学和药物遗传学研究

IF 6.3 2区医学

Clinical Pharmacology & Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-10-04 DOI: 10.1002/cpt.3462

Yawen Yuan, Wenting Hu, Changcheng Chen, Ruen Yao, Shunguo Zhang, Xiao Zhu, Bulong Xu, Zhonghui Huang, Shengyuan Zhang, Xuexian Wang, Mei Zheng, Xiaohui Huang, Joseph F Standing

{"title":"Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Studies Related to Vincristine-Induced Peripheral Neuropathy in Chinese Pediatric ALL Patients.","authors":"Yawen Yuan, Wenting Hu, Changcheng Chen, Ruen Yao, Shunguo Zhang, Xiao Zhu, Bulong Xu, Zhonghui Huang, Shengyuan Zhang, Xuexian Wang, Mei Zheng, Xiaohui Huang, Joseph F Standing","doi":"10.1002/cpt.3462","DOIUrl":"10.1002/cpt.3462","url":null,"abstract":"Vincristine (VCR) can cause vincristine-induced peripheral neuropathy (VIPN) during the treatment of acute lymphoblastic leukemia (ALL) and the mechanisms are complicated. The aim of this study was to investigate the influencing factors on the population pharmacokinetics (PopPK) and pharmacodynamics (PD) related to VIPN, including clearance routes, drug-drug interactions (DDI), and genetic characteristics. Pediatric patients being treated for ALL were recruited to PK study where VCR and its metabolite (M1) were measured using a novel assay. The incidence of VIPN was also recorded. DNA sequencing of relevant PK and PD genes was performed. PopPK and PK/PD models were developed, pharmacogenetic and DDI analyses were conducted. In total, 79 children were recruited. The results showed that allometric scaling, ABCB1-rs1128503 genotype, and posaconazole (POS) significantly improved the PopPK model fit. VIPN was significantly correlated with the exposure of VCR. Co-administration with POS shifted the effect curve for VIPN to the left, indicating increased VIPN risk at the same exposure levels. No significant effects on VIPN were observed for CYP3A5 (rs776746), CYP3A4 (rs2242480), CEP72 (rs924607), or various ABCB1 variants (rs1128503, rs2032582, rs1045642, rs4728709, rs4148737, and rs10276036), nor with the co-administration of fluconazole or dasatinib. In summary, co-administration of POS increased VCR exposure by 0.4-fold and raised the risk of VIPN, with an occurrence probability generally exceeding 0.7. Therapeutic drug monitoring of VCR in clinical practice may be necessary to enable appropriate dose adjustments and individualized treatment.","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"454-464"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374748","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}

引用次数: 0

Cerebral Ischemia Protection After Aneurysmal Subarachnoid Hemorrhage: CSF Nimodipine Levels After Intravenous Versus Oral Nimodipine Administration. 动脉瘤性蛛网膜下腔出血后的脑缺血保护：静脉注射与口服尼莫地平后的脑脊液尼莫地平水平。

IF 6.3 2区医学

Clinical Pharmacology & Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-11-19 DOI: 10.1002/cpt.3499

Miriam M Moser, Karl Rössler, Dorian Hirschmann, Leon Gramss, Ammar Tahir, Walter Plöchl, Johannes Herta, Andrea Reinprecht, Markus Zeitlinger, Arthur Hosmann

{"title":"Cerebral Ischemia Protection After Aneurysmal Subarachnoid Hemorrhage: CSF Nimodipine Levels After Intravenous Versus Oral Nimodipine Administration.","authors":"Miriam M Moser, Karl Rössler, Dorian Hirschmann, Leon Gramss, Ammar Tahir, Walter Plöchl, Johannes Herta, Andrea Reinprecht, Markus Zeitlinger, Arthur Hosmann","doi":"10.1002/cpt.3499","DOIUrl":"10.1002/cpt.3499","url":null,"abstract":"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 (AUC0-24) 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) (AUCCSF/AUCplasma). In contrast, nimodipine levels were significantly lower in both plasma (AUC0-24 298.32 ± 206.52 mg*h/L) and CSF (AUC0-24 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.","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"589-597"},"PeriodicalIF":6.3,"publicationDate":"2025-02-01","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}

引用次数: 0