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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 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-08 DOI: 10.1002/cpt.3465
Paarth Parekh, Jason Sherfey, Begum Alaybeyoglu, Murat Cirit

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.

临床前研究的准确临床转化仍然具有挑战性,这主要是由于物种特异性差异以及疾病和患者的异质性。最近的一项重要进展是开发了微观生理系统,该系统由多种人类细胞类型组成,可再现各自人类系统的关键特征,从而在药物开发过程中准确评估基本生理过程。然而,对于评估不同样本类型在不同使用环境(CoU)特异性通路中的相似性的定量方法,仍有未满足的需求。为了填补这一空白,本研究介绍了基于通路的相似性测量(PBSM)的开发情况,它利用 RNA-seq 数据和基于通路的信息来评估临床前模型与特定 CoU 的人体相关性。PBSM 提供了一种定量方法来比较临床前模型与人体组织的转录组相似性,这里显示的是肝脏和心脏组织的概念验证,从而改进了模型的选择和验证。因此,PBSM 可以成功支持临床前模型的 CoU 选择,评估不同基因组对相似性计算的影响,并区分各种体外和体内模型。PBSM 可以定量评估临床前模型与人体组织的相似性,促进模型选择,并提高对特定环境应用的理解,从而有可能缩小药物开发的转化差距。PBSM 可作为增强体外模型生理相关性的基础,并支持开发更有效的治疗干预措施。
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引用次数: 0
Value of Pharmacogenetic Testing Assessed with Real-World Drug Utilization and Genotype Data. 利用真实世界的药物使用情况和基因型数据评估药物基因检测的价值。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-04 DOI: 10.1002/cpt.3458
Kaisa Litonius, Noora Kulla, Petra Falkenbach, Kati Kristiansson, E Katriina Tarkiainen, Liisa Ukkola-Vuoti, Kristiina Cajanus, Mari Korhonen, Sofia Khan, Johanna Sistonen, Arto Orpana, Mats Lindstedt, Tommi Nyrönen, Markus Perola, Miia Turpeinen, Ville Kytö, Aleksi Tornio, Mikko Niemi

Implementation of pharmacogenetic testing in clinical care has been slow and with few exceptions is hindered by the lack of real-world evidence on how to best target testing. In this retrospective register-based study, we analyzed a nationwide cohort of 1,425,000 patients discharged from internal medicine or surgical wards and a cohort of 2,178 university hospital patients for purchases and prescriptions of pharmacogenetically actionable drugs. Pharmacogenetic variants were obtained from whole genome genotype data for a subset (n = 930) of the university hospital patients. We investigated factors associated with receiving pharmacogenetically actionable drugs and developed a literature-based cost-benefit model for pre-emptive pharmacogenetic panel testing. In a 2-year follow-up, 60.4% of the patients in the nationwide cohort purchased at least one pharmacogenetically actionable drug, most commonly ibuprofen (25.0%) and codeine (19.4%). Of the genotyped subset, 98.8% carried at least one actionable pharmacogenetic genotype and 23.3% had at least one actionable gene-drug pair. Patients suffering from musculoskeletal or cardiovascular diseases were more prone to receive pharmacogenetically actionable drugs during inpatient episode. The cost-benefit model included frequently dispensed drugs in the university hospital cohort, comprising ondansetron (19.4%), simvastatin (7.4%), clopidogrel (5.0%), warfarin (5.1%), (es)citalopram (5.3%), and azathioprine (0.5%). For untargeted pre-emptive pharmacogenetic testing of all university hospital patients, the model indicated saving €17.49 in direct healthcare system costs per patient in 2 years without accounting for the cost of the test itself. Therefore, it might be reasonable to target pre-emptive pharmacogenetic testing to patient groups most likely to receive pharmacogenetically actionable drugs.

药物基因检测在临床治疗中的应用一直进展缓慢,除少数例外情况外,还因缺乏关于如何最有针对性地进行检测的实际证据而受到阻碍。在这项以登记为基础的回顾性研究中,我们分析了全国范围内 142.5 万名内科或外科病房出院患者的队列以及 2178 名大学医院患者的队列,了解他们购买和开具药物遗传学可操作性药物处方的情况。药物基因变异是从大学医院患者子集(n = 930)的全基因组基因型数据中获得的。我们调查了与接受药物遗传学可操作性药物相关的因素,并开发了一个基于文献的先期药物遗传学面板检测成本效益模型。在为期 2 年的随访中,全国范围内有 60.4% 的患者至少购买了一种药物基因作用药物,其中最常见的是布洛芬(25.0%)和可待因(19.4%)。在基因分型子群中,98.8%的人携带至少一种可操作的药物基因型,23.3%的人拥有至少一对可操作的基因-药物配对。患有肌肉骨骼或心血管疾病的患者在住院期间更容易接受可作用的药物。成本效益模型包括大学医院队列中的常用药物,包括昂丹司琼(19.4%)、辛伐他汀(7.4%)、氯吡格雷(5.0%)、华法林(5.1%)、(ES)西酞普兰(5.3%)和硫唑嘌呤(0.5%)。如果对所有大学医院的患者进行无针对性的先期药物基因检测,模型显示,在不考虑检测成本的情况下,2 年内每位患者可节省 17.49 欧元的直接医疗系统成本。因此,针对最有可能接受药物遗传学可操作性药物的患者群体进行先期药物遗传学检测可能是合理的。
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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 Q1 PHARMACOLOGY & PHARMACY Pub 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

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.

长春新碱(VCR)在急性淋巴细胞白血病(ALL)的治疗过程中可引起长春新碱诱导的周围神经病变(VIPN),其机制十分复杂。本研究旨在调查与VIPN相关的群体药代动力学(PopPK)和药效学(PD)的影响因素,包括清除途径、药物间相互作用(DDI)和遗传特征。PK研究招募了接受ALL治疗的儿童患者,使用一种新型检测方法测量VCR及其代谢物(M1)。同时还记录了VIPN的发生率。对相关的 PK 和 PD 基因进行了 DNA 测序。建立了 PopPK 和 PK/PD 模型,并进行了药物遗传学和 DDI 分析。共招募了 79 名儿童。结果显示,异速缩放、ABCB1-rs1128503 基因型和泊沙康唑(POS)能显著提高 PopPK 模型的拟合度。VIPN 与 VCR 暴露有明显的相关性。与 POS 同时给药会使 VIPN 的效应曲线向左移动,这表明在相同的暴露水平下,VIPN 的风险会增加。CYP3A5(rs776746)、CYP3A4(rs2242480)、CEP72(rs924607)或各种ABCB1变体(rs1128503、rs2032582、rs1045642、rs4728709、rs4148737和rs10276036)对VIPN没有明显影响,同时服用氟康唑或达沙替尼也没有明显影响。总之,合用 POS 会使 VCR 暴露增加 0.4 倍,并增加发生 VIPN 的风险,发生概率一般超过 0.7。在临床实践中可能有必要对 VCR 进行治疗药物监测,以便进行适当的剂量调整和个体化治疗。
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引用次数: 0
Pharmacokinetic, Safety, and Pharmacodynamic Profiles of Saroglitazar Magnesium in Cholestatic Cirrhosis With Hepatic Impairment and Participants With Renal Impairment. 肝功能受损的胆汁淤积性肝硬化患者和肾功能受损者服用沙格列扎镁的药代动力学、安全性和药效学概况
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-02 DOI: 10.1002/cpt.3450
Raj Vuppalanchi, Mary M Cruz, Taufik Momin, Farheen Shaikh, Kimberly Swint, Harilal Patel, Deven Parmar

Saroglitazar magnesium, a dual PPAR α/γ agonist, currently in Phase III for treating primary biliary cholangitis (PBC), was evaluated for its pharmacokinetic (PK) profile, safety, and pharmacodynamics in participants with cholestatic liver disease (CLD) across different levels of hepatic impairment (HI) and participants with severe renal impairment (RI). Three PK studies comparing saroglitazar with healthy controls were conducted: Study 1 involved daily oral doses of 1 or 2 mg for 4 weeks in 12 PBC cirrhosis participants with mild or moderate HI; Study 2 assessed single-dose PK (2 or 4 mg) in eight non-cirrhotic CLD participants; Study 3 evaluated single-dose PK (2 mg) in eight participants with severe RI. On day 1, saroglitazar exposure increased by 14.6-42% in mild HI vs. normal, but by day 28, levels were similar, indicating no accumulation. In moderate HI, exposure was significantly increased by 50.4-85% on days 1 and 28, with 34-46% lower clearance despite a similar half-life. The moderate HI group had a 59% higher exposure than the non-cirrhotic group. Saroglitazar (1 and 2 mg) reduced alkaline phosphatase (ALP) levels by 17-40% after 4 weeks in participants with abnormal baseline ALP. Single-dose PK in non-cirrhotic CLD (2 and 4 mg) and severe RI (2 mg) was comparable to matched controls without significant safety issues. Overall, saroglitazar (1 and 2 mg) was safe and well-tolerated in cholestatic cirrhosis with mild HI and participants with severe RI without major PK changes. Moderate HI increased exposure and decreased clearance without any safety concerns.

沙格列扎镁是一种 PPAR α/γ 双激动剂,目前正处于治疗原发性胆汁性胆管炎 (PBC) 的 III 期临床阶段,研究人员评估了它在不同肝功能损害程度 (HI) 的胆汁淤积性肝病 (CLD) 患者和严重肾功能损害 (RI) 患者中的药代动力学 (PK) 特征、安全性和药效学。共进行了三项 PK 研究,将沙格列扎与健康对照组进行比较:研究 1 对 12 名轻度或中度 HI 的 PBC 肝硬化患者进行了为期 4 周、每天口服 1 或 2 毫克的研究;研究 2 评估了 8 名非肝硬化 CLD 患者的单剂量 PK(2 或 4 毫克);研究 3 评估了 8 名严重 RI 患者的单剂量 PK(2 毫克)。第 1 天,与正常人相比,轻度 HI 患者的沙格列扎尔暴露量增加了 14.6-42%,但到第 28 天,暴露量水平相似,表明没有蓄积。在中度 HI 中,第 1 天和第 28 天的暴露量显著增加了 50.4-85%,尽管半衰期相似,但清除率降低了 34-46%。中度 HI 组的暴露量比非肝硬化组高 59%。沙格列扎尔(1 毫克和 2 毫克)可在 4 周后将基线 ALP 异常者的碱性磷酸酶 (ALP) 水平降低 17-40%。非肝硬化CLD(2毫克和4毫克)和严重RI(2毫克)患者的单剂量PK值与匹配对照组相当,没有明显的安全性问题。总体而言,沙格列扎尔(1 毫克和 2 毫克)在胆汁淤积性肝硬化轻度 HI 和重度 RI 患者中安全且耐受性良好,没有重大 PK 变化。中度 HI 会增加暴露量并降低清除率,但不存在任何安全问题。
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引用次数: 0
New Drug Development Strategy in Japan: Flexibility in Guideline Adherence. 日本的新药开发战略:日本新药开发战略:遵守指南的灵活性。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-02 DOI: 10.1002/cpt.3456
Mihoko Kobayashi, Mamoru Narukawa

Recently, a new type of drug lag, known as "drug loss" has emerged in Japan. It is a condition where the development of a drug approved in other countries has not been initiated in Japan. For 265 new drugs approved in the United States or Europe during 2010-2020, only 31% had commenced development in Japan as of December 31, 2020. A characteristic feature of Japanese guidelines on new drug development is that, in principle, clinical trial data in Japanese participants are required in each study phase. Given key players in new drug development are shifting from large pharmaceutical companies to emerging biopharma companies, primarily based outside Japan, the necessity for Japanese data may contribute to the drug lag. This study aimed to clarify the guideline adherence to new drug applications in Japan. Of the 159 new drugs approved in Japan between April 2019 and March 2024, the clinical data packages for almost all drugs included both pharmacokinetic (PK) data and efficacy and safety data in Japanese participants, irrespective of the study phase or design. We identified three flexible development approaches: the absence of Japanese dose-response data (39.6%), absence of Japanese confirmatory data generated from phase III randomized controlled trials (35.2%), and post-hoc Japanese PK data (43.0%, 34/79). Biologics, orphan drug designation, antineoplastic agents, and same applicant and originator were identified as factors significantly associated with these flexibilities. The results will help foreign companies, including emerging biopharmas, in formulating effective new drug development strategies, potentially alleviating the drug lag in Japan.

最近,日本出现了一种新的药物滞后现象,即 "药物流失"。这种情况是指在其他国家获得批准的药物尚未在日本开始研发。截至 2020 年 12 月 31 日,在 2010-2020 年期间美国或欧洲批准的 265 种新药中,只有 31% 在日本开始研发。日本新药开发指导方针的一个特点是,原则上每个研究阶段都需要日本参与者的临床试验数据。鉴于新药开发的主要参与者正从大型制药公司转向新兴的生物制药公司(主要总部设在日本以外),因此必须提供日本数据可能会导致新药开发滞后。本研究旨在阐明日本新药申请的指导原则遵守情况。在 2019 年 4 月至 2024 年 3 月期间日本批准的 159 种新药中,无论研究阶段或设计如何,几乎所有药物的临床数据包都包括药代动力学 (PK) 数据以及日本参与者的疗效和安全性数据。我们发现了三种灵活的开发方式:缺乏日本的剂量反应数据(39.6%)、缺乏由 III 期随机对照试验产生的日本确证数据(35.2%)以及事后日本 PK 数据(43.0%,34/79)。生物制剂、指定孤儿药、抗肿瘤药以及同一申请人和原研者被认为是与这些灵活性密切相关的因素。研究结果将有助于外国公司(包括新兴生物制药公司)制定有效的新药开发战略,从而有可能缓解日本的药物滞后问题。
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引用次数: 0
Reply to: "Questioning Conclusions and Statements on the German HTA System: A Critical Perspective". 答复"质疑有关德国 HTA 系统的结论和声明:批判性视角"。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-01 DOI: 10.1002/cpt.3452
James Harnett, Julien Heidt, Ruben G W Quek, Laura Walsh
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引用次数: 0
Harnessing Pharmacogenomics in Clinical Research on Psychedelic-Assisted Therapy. 在迷幻辅助疗法的临床研究中利用药物基因组学。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-30 DOI: 10.1002/cpt.3459
Andreas Halman, Rachel Conyers, Claire Moore, Dhrita Khatri, Jerome Sarris, Daniel Perkins

Psychedelics have recently re-emerged as potential treatments for various psychiatric conditions that impose major public health costs and for which current treatment options have limited efficacy. At the same time, personalized medicine is increasingly being implemented in psychiatry to provide individualized drug dosing recommendations based on genetics. This review brings together these topics to explore the utility of pharmacogenomics (a key component of personalized medicine) in psychedelic-assisted therapies. We summarized the literature and explored the potential implications of genetic variability on the pharmacodynamics and pharmacokinetics of psychedelic drugs including lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), ibogaine and 3,4-methylenedioxymethamphetamine (MDMA). Although existing evidence is limited, particularly concerning pharmacodynamics, studies investigating pharmacokinetics indicate that genetic variants in drug-metabolizing enzymes, such as cytochrome P450, impact the intensity of acute psychedelic effects for LSD and ibogaine, and that a dose reduction for CYP2D6 poor metabolizers may be appropriate. Furthermore, based on the preclinical evidence, it can be hypothesized that CYP2D6 metabolizer status might contribute to altered acute psychedelic experiences with 5-MeO-DMT and psilocybin when combined with monoamine oxidase inhibitors. In conclusion, considering early evidence that genetic factors can influence the effects of certain psychedelics, we suggest that pharmacogenomic testing should be further investigated in clinical research. This is necessary to evaluate its utility in improving the safety and therapeutic profile of psychedelic therapies and a potential future role in personalizing psychedelic-assisted therapies, should these treatments become available.

近来,迷幻药再次成为治疗各种精神疾病的潜在疗法,这些疾病造成了巨大的公共卫生成本,而目前的治疗方案对这些疾病的疗效有限。与此同时,个性化医疗也越来越多地应用于精神病学领域,以提供基于遗传学的个体化药物剂量建议。本综述汇集了这些主题,探讨药物基因组学(个性化医疗的关键组成部分)在迷幻辅助疗法中的应用。我们总结了相关文献,并探讨了遗传变异对迷幻药(包括麦角酰二乙胺(LSD)、西洛赛宾、N,N-二甲基色胺(DMT)、5-甲氧基-N,N-二甲基色胺(5-MeO-DMT)、伊博碱和 3,4-亚甲二氧基甲基苯丙胺(MDMA))的药效学和药代动力学的潜在影响。虽然现有的证据有限,尤其是在药效学方面,但对药代动力学的研究表明,药物代谢酶(如细胞色素 P450)的基因变异会影响迷幻剂和伊博格碱的急性迷幻效果的强度,因此对 CYP2D6 代谢较差的人可能应适当减少剂量。此外,根据临床前的证据,可以假设 CYP2D6 代谢者的状态可能会导致 5-MeO-DMT 和西洛赛宾与单胺氧化酶抑制剂合用时的急性迷幻体验发生改变。总之,考虑到有早期证据表明遗传因素会影响某些迷幻剂的作用,我们建议在临床研究中进一步调查药物基因组测试。这对于评估药物基因组学在提高迷幻药疗法的安全性和治疗效果方面的作用,以及在迷幻药辅助疗法个性化方面的潜在作用(如果这些疗法可用的话)都是非常必要的。
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引用次数: 0
Optimal Trough Concentration of Tacrolimus in Pediatric Patients With Primary Nephrotic Syndrome. 原发性肾病综合征儿科患者体内他克莫司的最佳低浓度。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-30 DOI: 10.1002/cpt.3448
Hui Wang, Maochang Liu, Xiaowen Wang, Hui Peng, Changhe Niu, Mengting Li, Ping Gao

The trough concentration (C0) of tacrolimus in children with nephrotic syndrome (NS) has rarely been explored, so its target level was based on transplant research. This study aimed to determine the optimal tacrolimus C0 in NS children. Data from primary NS children treated with tacrolimus at Wuhan Children's Hospital in the last 10 years were retrospectively collected. According to the cutoff C0 analyzed by receiver-operator characteristics (ROC) analysis, patients were divided into very low- (< 4 ng/mL), low- (4-5 ng/mL), medium- (5-7 ng/mL), and high-concentration (7-10 ng/mL) groups. A total of 196 patients were enrolled for primary outcome analysis. Compared to medium-concentration group, only the very low-concentration group obtained significant inferior primary outcomes, including overall remission rate, relapse-free survival rate, and relapse rate at 6 months. For secondary outcomes, the very low-concentration group experienced more frequent treatment failure in 12 months, whereas the high-concentration group suffered a higher risk of adverse events than the medium-concentration group. For steroid-resistant NS, very low- and low-concentration groups required longer time to achieve remission compared to medium-concentration group. For steroid-sensitive NS, the very low-concentration group suffered a higher relapse frequency than medium-concentration group. Lastly, the dose of tacrolimus required for children with different CYP3A5 genotypes with or without Wuzhi capsules was analyzed. In conclusion, tacrolimus may be targeted to C0 of 4-7 ng/mL during the first 6 months in children with NS. For steroid-resistant NS, C0 of 5-7 ng/mL can achieve a rapid remission.

肾病综合征(NS)患儿的他克莫司谷浓度(C0)很少被探讨,因此其目标水平是基于移植研究。本研究旨在确定肾病综合征患儿的最佳他克莫司 C0。本研究回顾性收集了武汉市儿童医院近10年来接受他克莫司治疗的原发性肾病综合征患儿的数据。根据接受者-操作者特征(ROC)分析得出的C0临界值,NS患儿在最初6个月中被分为极低(0为4-7纳克/毫升)和极高(0为4-7纳克/毫升)两类。对于类固醇耐药的NS,5-7纳克/毫升的C0可使病情迅速缓解。
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引用次数: 0
Extrapolation of Upadacitinib Efficacy in Juvenile Idiopathic Arthritis Leveraging Pharmacokinetics, Exposure–Response Models, and Real-World Patient Data 利用药代动力学、暴露-反应模型和真实世界患者数据推断乌帕他替尼对幼年特发性关节炎的疗效
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-29 DOI: 10.1002/cpt.3441
Yuli Qian, Louisa Schlachter, Doerthe Eckert, Sven Stodtmann, Anna Shmagel, Yi Peng, Wei Liu, Mohamed-Eslam F. Mohamed

Juvenile idiopathic arthritis (JIA) is the most prevalent pediatric rheumatic disease. While disease-modifying antirheumatic drugs (DMARDs), especially biologics, have greatly transformed the management of JIA, there remain some unmet medical needs that require new treatment options. The objective of this work was to describe and apply a modeling and simulation approach to extrapolate upadacitinib efficacy from the adult diseases, rheumatoid arthritis (RA) and psoriatic arthritis (PsA), to their respective pediatric diseases, polyarticular course JIA (pcJIA), and juvenile PsA (JPsA). A population pharmacokinetic model characterized upadacitinib pharmacokinetics in pediatric patients using data from two phase I studies in pediatric patients with pcJIA (N = 51) or atopic dermatitis (N = 33). Efficacy simulations were conducted using previously developed exposure–response models in adults with RA and PsA. Real-world pcJIA and JPsA patient databases were leveraged to construct representative patient profiles for the targeted population. Following administration of the proposed weight-based dosing regimen, the model-predicted median upadacitinib plasma exposures in pediatric patients were within 20% of those in adult RA and PsA patients receiving the approved adult regimen. Simulations demonstrate that upadacitinib efficacy in pcJIA and JPsA is predicted to be non-inferior to that in adults with RA or PsA, respectively. The results of this work enabled recent approvals of upadacitinib for the treatment of polyarticular JIA and JPsA in the United States. Upadacitinib safety in pediatrics is being further evaluated in ongoing clinical trials.

幼年特发性关节炎(JIA)是发病率最高的儿科风湿病。虽然改变病情抗风湿药(DMARDs),尤其是生物制剂,已经大大改变了JIA的治疗方法,但仍有一些医疗需求未得到满足,需要新的治疗方案。这项工作的目的是描述并应用一种建模和模拟方法,将达帕替尼的疗效从成人疾病类风湿性关节炎(RA)和银屑病关节炎(PsA)推断到各自的儿科疾病多关节病程JIA(pcJIA)和幼年PsA(JPsA)。一个群体药代动力学模型利用在患有pcJIA(51例)或特应性皮炎(33例)的儿科患者中进行的两项I期研究的数据,描述了达达替尼在儿科患者中的药代动力学特征。疗效模拟是利用之前开发的成人 RA 和 PsA 暴露-反应模型进行的。利用真实世界的 pcJIA 和 JPsA 患者数据库,为目标人群建立了具有代表性的患者档案。在采用建议的基于体重的给药方案后,模型预测的儿科患者的中位upadacitinib血浆暴露量与接受已获批准的成人方案治疗的成人RA和PsA患者的暴露量相差不到20%。模拟结果表明,预计奥达帕替尼对pcJIA和JPsA的疗效分别不劣于对成人RA或PsA的疗效。这项工作的结果使美国最近批准了奥达替尼用于治疗多关节JIA和JPsA。目前正在进行的临床试验中进一步评估奥达替尼对儿科患者的安全性。
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引用次数: 0
Quantitative Systems Pharmacology Models: Potential Tools for Advancing Drug Development for Rare Diseases 定量系统药理学模型:促进罕见病药物开发的潜在工具。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-28 DOI: 10.1002/cpt.3451
Susana Neves-Zaph, Chanchala Kaddi

Rare diseases, affecting millions globally, present significant drug development challenges. This is due to the limited patient populations and the unique pathophysiology of these diseases, which can make traditional clinical trial designs unfeasible. Quantitative Systems Pharmacology (QSP) models offer a promising approach to expedite drug development, particularly in rare diseases. QSP models provide a mechanistic representation of the disease and drug response in virtual patients that can complement routinely applied empirical modeling and simulation approaches. QSP models can generate digital twins of actual patients and mechanistically simulate the disease progression of rare diseases, accounting for phenotypic heterogeneity. QSP models can also support drug development in various drug modalities, such as gene therapy. Impactful QSP models case studies are presented here to illustrate their value in supporting various aspects of drug development in rare indications. As these QSP model applications continue to mature, there is a growing possibility that they could be more widely integrated into routine drug development steps. This integration could provide a robust framework for addressing some of the inherent challenges in rare disease drug development.

罕见病影响着全球数百万人,给药物开发带来了巨大挑战。这是因为这些疾病的患者群体有限,病理生理学独特,传统的临床试验设计难以实现。定量系统药理学(QSP)模型为加快药物开发,尤其是罕见病的药物开发提供了一种前景广阔的方法。QSP 模型提供了虚拟患者的疾病和药物反应的机理表述,可以补充常规应用的经验建模和模拟方法。QSP 模型可以生成实际患者的数字双胞胎,并从机理上模拟罕见病的疾病进展,同时考虑表型异质性。QSP 模型还可以支持基因治疗等各种药物模式的药物开发。本文介绍了具有影响力的 QSP 模型案例研究,以说明它们在支持罕见适应症药物开发的各个方面所具有的价值。随着这些 QSP 模型应用的不断成熟,它们越来越有可能被更广泛地整合到常规药物开发步骤中。这种整合可以为解决罕见病药物开发中的一些固有挑战提供一个强大的框架。
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Clinical Pharmacology & Therapeutics
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