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Effects of Cimetidine and Dolutegravir on the Endogenous Drug-Drug Interaction Biomarkers for Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Protein 1 in Healthy Volunteers. 西咪替丁和多罗替拉韦对健康志愿者体内有机阳离子转运体 2 和多药与毒素挤出蛋白 1 的内源性药物-药物相互作用生物标记物的影响
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-05 DOI: 10.1002/cpt.3482
Tomoki Koishikawa, Kaku Fujiwara, Kunal Taskar, Maciej J Zamek-Gliszczynski, Kenta Yoshida, Xiaoyan Chu, Hideki Hirabayashi, Jialin Mao, Kevin Rockich, Tadayuki Takashima, Yoshiyuki Yamaura, Yurong Lai, Yukana Tomoda, Tomoko Kito, Kazuya Maeda, Kenichi Furihata, Yuichi Sugiyama, Hiroyuki Kusuhara

This study was designed to assess the quantitative performance of endogenous drug-drug interaction (DDI) biomarkers (N1-methylnicotinamide (1-NMN), N1-methyladenosine (m1A), and creatinine) for the organic cation transporters, OCT2 and MATE1/2K in the kidney. Ten healthy volunteers received cimetidine (400 and 800 mg, single dose) or dolutegravir (50 mg, twice a day) together with metformin (500 mg). Cimetidine and dolutegravir were considered to act mainly as MATE1/2K and OCT2 inhibitors, respectively. The renal clearance (CLr) of metformin was decreased by 15.5% and 42.5% by cimetidine 400 and 800 mg, and by 26.8% and 56.9% by dolutegravir first and fifth doses, respectively. CLr ratio (CLrR) of 1-NMN were 0.93 and 0.64 for cimetidine 400 and 800 mg, and 0.87 and 0.47 for dolutegravir first and fifth doses, respectively. CLrR of m1A was less than that of 1-NMN: 1.0 and 0.80 for cimetidine 400 and 800 mg, and 0.77 and 0.71 for dolutegravir first and fifth doses, respectively. CLr of creatinine was significantly decreased only by cimetidine 800 mg. Individual CLrR of 1-NMN and m1A showed a positive correlation with the corresponding CLrR of metformin with r2 of 0.58 and 0.55, respectively. When evaluated individually, m1A showed a better correlation during cimetidine periods (r2 0.64) than 1-NMN (r2 0.36), but vice versa during dolutegravir periods (r2 1-NMN, 0.80; m1A, 0.32). These results suggest that 1-NMN and m1A might be more promising than creatinine as endogenous biomarkers for quantitatively assessing the DDI potential of investigational drugs for OCT2 and MATE1/2K based on their CLrR change.

本研究旨在评估内源性药物相互作用(DDI)生物标记物(N1-甲基烟酰胺(1-NMN)、N1-甲基腺苷(m1A)和肌酐)对肾脏中有机阳离子转运体 OCT2 和 MATE1/2K 的定量作用。十名健康志愿者在服用二甲双胍(500 毫克)的同时,还服用了西咪替丁(400 毫克和 800 毫克,单剂量)或多替拉韦(50 毫克,一天两次)。西咪替丁和多仑特拉韦分别被认为是主要的 MATE1/2K 和 OCT2 抑制剂。西咪替丁 400 毫克和 800 毫克可使二甲双胍的肾清除率(CLr)分别降低 15.5%和 42.5%,多鲁曲韦第一剂量和第五剂量可使二甲双胍的肾清除率分别降低 26.8%和 56.9%。西咪替丁 400 毫克和 800 毫克的 1-NMN CLrr 比率(CLrR)分别为 0.93 和 0.64,多仑特韦酯第一剂和第五剂的 1-NMN CLrr 比率(CLrR)分别为 0.87 和 0.47。m1A 的 CLrR 低于 1-NMN:西咪替丁 400 毫克和 800 毫克的 CLrR 分别为 1.0 和 0.80,多鲁曲韦第一剂和第五剂的 CLrR 分别为 0.77 和 0.71。只有西咪替丁 800 毫克能显著降低肌酐的 CLrR。1-NMN 和 m1A 的单个 CLrR 与二甲双胍的相应 CLrR 呈正相关,r2 分别为 0.58 和 0.55。单独评估时,m1A 在西咪替丁期间的相关性(r2 0.64)优于 1-NMN(r2 0.36),但在多罗替拉韦期间则相反(r2 1-NMN,0.80;m1A,0.32)。这些结果表明,与肌酐相比,1-NMN 和 m1A 可能更适合作为内源性生物标记物,用于根据其 CLrR 变化定量评估 OCT2 和 MATE1/2K 研究药物的 DDI 潜力。
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引用次数: 0
Correction to Beyond MABEL: An Integrative Approach to First in Human Dose Selection of Immunomodulators by the Health and Environmental Sciences Institute (HESI) Immuno-Safety Technical Committee (ITC). 健康与环境科学研究所(HESI)免疫安全技术委员会(ITC)对《超越 MABEL:免疫调节剂人体首次剂量选择的综合方法》的更正。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-04 DOI: 10.1002/cpt.3489
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引用次数: 0
Sex-Dependent Effects of CYP2D6 on the Pharmacokinetics of Berberine in Humans. CYP2D6 对人体小檗碱药代动力学的性别依赖性影响
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-03 DOI: 10.1002/cpt.3454
Jonas A Blöcher, Marleen J Meyer-Tönnies, Felix Morof, Vincent Rönnpagel, Jonas Bethmann, Marcus Vollmer, Stefan Engeli, Mladen V Tzvetkov

An over-the-counter product berberine (a major alkaloid in goldenseal) is a substrate of the uptake transporter OCT1 and the metabolizing enzyme CYP2D6. The two genes exhibit common functional polymorphisms. Approximately 9% of Europeans and white Americans are either poor CYP2D6 metabolizers or poor OCT1 transporters. In this study, we investigated the effects of OCT1 and CYP2D6 polymorphisms on berberine pharmacokinetics in humans. We confirmed in vitro that berberine is an OCT1 substrate (KM of 7.0 μM, CLint of 306 ± 29 μL/min/mg). Common OCT1 alleles *3 to *6 showed uptake reduced by at least 65% and Oct1/2 knockout mice showed 3.2-fold higher AUCs in liver perfusion experiments. However, in humans, poor OCT1 transporters did not show any differences in berberine pharmacokinetics compared with reference participants. In contrast, CYP2D6 polymorphisms significantly affected berberine metabolism, but exclusively in females. Females who were poor CYP2D6 metabolizers had an 80% lower M1-to-berberine ratio. General linear model analyses suggest strong synergistic, rather than additive, effects between female sex and CYP2D6 genotype. Overall, berberine displayed low oral bioavailability, yet females had a 2.8-fold higher AUC and a 3.6-fold higher Cmax than males (P < 0.001). These effects were only partially attributable to the sex-CYP2D6 genotype interaction. In conclusion, despite berberine being an OCT1 substrate, OCT1 deficiency did not affect berberine pharmacokinetics in humans. In contrast, CYP2D6 emerges as a critical enzyme for berberine metabolism in females, but not in males, highlighting sex-specific differences. We suggest that factors beyond CYP2D6 metabolism are determining berberine's systemic exposure, especially in males (NCT05463003).

一种非处方产品小檗碱(金线莲中的一种主要生物碱)是吸收转运体 OCT1 和代谢酶 CYP2D6 的底物。这两种基因具有共同的功能多态性。约有 9% 的欧洲人和美国白人的 CYP2D6 代谢能力较差或 OCT1 转运能力较差。在这项研究中,我们调查了 OCT1 和 CYP2D6 多态性对人体小檗碱药代动力学的影响。我们在体外证实了小檗碱是一种 OCT1 底物(KM 为 7.0 μM,CLint 为 306 ± 29 μL/min/mg)。常见的 OCT1 等位基因 *3 至 *6 的吸收率至少降低了 65%,Oct1/2 基因敲除小鼠在肝脏灌注实验中的 AUC 高出 3.2 倍。然而,在人体中,OCT1 转运能力差的人与参照参与者相比,在小檗碱药代动力学方面没有显示出任何差异。相比之下,CYP2D6 多态性会显著影响小檗碱的代谢,但仅限于女性。CYP2D6 代谢较差的女性的 M1 与小檗碱的比值低 80%。一般线性模型分析表明,女性性别与 CYP2D6 基因型之间存在很强的协同效应,而不是相加效应。总体而言,小檗碱的口服生物利用度较低,但女性的 AUC 和 Cmax 分别是男性的 2.8 倍和 3.6 倍(P<0.05)。
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引用次数: 0
Real-World Effectiveness of All-Oral Direct-Acting Antivirals in Patients With Hepatitis C Virus-Related HCC. 全口服直接作用抗病毒药物对丙型肝炎病毒相关 HCC 患者的实际疗效。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-03 DOI: 10.1002/cpt.3481
Shao-Hsuan Chang, Roniel Cabrera, Jihaeng Heo, Chanhyun Park, Jingchuan Guo, Haesuk Park

The association between direct-acting antiviral (DAA) treatment and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is currently unclear. Hence, we aim to assess the association between DAA treatment and mortality rate among Medicare beneficiaries with HCV-related HCC. This retrospective cohort study screened 19,813 adults in 2013-2019 Surveillance, Epidemiology, and End Results data linked with Medicare data. Patients with HCV-related HCC initiating DAA therapy after their first HCC diagnosis were compared with patients with HCV-related HCC who received no HCV treatment. After inverse probability treatment weighting, multivariable Cox proportional hazards models compared mortality rates between the groups. Subgroup and sensitivity analyses were based on HCC stage (early vs. advanced), type of HCC treatment (curative, palliative, none), and DAA treatment duration. In total 3,777 patients with HCV-related HCC were identified (mean age: 68.2 years, 75.2% male, 61.8% White), of whom 19% initiated DAA therapy. Crude incidence mortality rates were 17.9 and 90.7 deaths per 100 person-years in the DAA and HCV-untreated groups, respectively. Cox regression models indicated that DAA therapy was associated with decreased risk of all-cause mortality (adjusted hazard ratio, 0.33; 95% CI 0.31-0.36). Median survival time was 45.7 (95% CI 40.9-57.9) months in the DAA group and 7.7 (95% CI 7.3-8.2) months in the HCV-untreated group (P < 0.001). All subgroup and sensitivity analyses were consistent with the main analyses. DAA therapy was associated with survival benefits for patients with HCV-related HCC regardless of the stage or type of HCC treatment and should not be withheld from this population of Medicare beneficiaries.

直接作用抗病毒药物(DAA)治疗与丙型肝炎病毒(HCV)相关肝细胞癌(HCC)之间的关系目前尚不清楚。因此,我们旨在评估DAA治疗与患有HCV相关HCC的医保受益人死亡率之间的关系。这项回顾性队列研究从 2013-2019 年与医疗保险数据关联的监测、流行病学和最终结果数据中筛选了 19813 名成人。首次诊断出HCC后开始接受DAA治疗的HCV相关HCC患者与未接受HCV治疗的HCV相关HCC患者进行了比较。经过逆概率治疗加权后,多变量 Cox 比例危险模型比较了两组患者的死亡率。根据HCC分期(早期与晚期)、HCC治疗类型(治愈性、缓解性、无)和DAA治疗持续时间进行了亚组和敏感性分析。共确定了 3,777 名 HCV 相关 HCC 患者(平均年龄:68.2 岁,75.2% 为男性,61.8% 为白人),其中 19% 接受了 DAA 治疗。DAA组和HCV未治疗组的粗发病死亡率分别为每100人年17.9例和90.7例。Cox回归模型显示,DAA疗法与全因死亡风险降低有关(调整后危险比为0.33;95% CI为0.31-0.36)。DAA 组的中位生存时间为 45.7(95% CI 40.9-57.9)个月,HCV 未治疗组的中位生存时间为 7.7(95% CI 7.3-8.2)个月(P<0.05)。
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引用次数: 0
Model-Informed Approach to Recommend Burosumab Dosing Regimens for Pediatric and Adult Patients With the Ultrarare Disease Tumor-Induced Osteomalacia. 以模型为基础的方法为儿童和成人超早期肿瘤诱发骨软化症患者推荐布罗苏单抗剂量方案
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-24 DOI: 10.1002/cpt.3468
Matthew W Hruska, Lamia Sid-Otmane, Nathalie H Gosselin, Emilia Quattrocchi, Sun Ku Lee, Mary Ann Mascelli, Krina Mehta, Suzanne M Jan de Beur, Douglas Marsteller

Burosumab is approved for the treatment of hypophosphatemia in persistent tumor-induced osteomalacia. This work exemplifies a model-informed drug development approach that evaluated burosumab pharmacokinetics and pharmacokinetic/pharmacodynamics in the ultrarare tumor-induced osteomalacia population to support adult and pediatric dosing. Data from tumor-induced osteomalacia participants were combined with data from X-linked hypophosphatemia to understand pharmacokinetic and pharmacokinetic/pharmacodynamic characteristics and covariates specific to tumor-induced osteomalacia. Pharmacokinetic and pharmacokinetic/pharmacodynamic simulations were performed using final models to support dosing recommendations for adults and extrapolation to pediatric patients. Burosumab pharmacokinetics were described using a one-compartment model with first-order absorption and body weight as a significant covariate. Pharmacokinetic/pharmacodynamic relationships were described using a sigmoidal Emax model with significant covariates of baseline fibroblast growth factor 23 on baseline fasting serum phosphate and potency of burosumab response and tumor-induced osteomalacia disease state resulting in a steep slope of response; however, the covariates are not clinically meaningful. Simulations demonstrated that, in pediatric patients, starting doses of burosumab 0.3 and 0.4 mg/kg every 2 weeks at steady state would achieve normal serum phosphate levels in ≥ 30% of patients with relatively low risk of hyperphosphatemia (< 3%). In adults, burosumab 0.3 and 0.5 mg/kg every 4 weeks achieves similar percentages of responders and a relative low risk of hyperphosphatemia (< 7%). Serum phosphate titration-based burosumab dosing increased the probability of achieving normal serum phosphate levels. The models supported a model-informed drug development approach for global approvals of titration-based burosumab dosing, guided by monitoring fasting serum phosphate levels.

布罗苏单抗被批准用于治疗持续性肿瘤诱导的骨软化症中的低磷血症。这项工作体现了一种以模型为依据的药物开发方法,该方法评估了布罗苏单抗在超罕见肿瘤诱导性骨软化症人群中的药代动力学和药动学/药效学,以支持成人和儿童用药。将肿瘤诱导性骨软化症患者的数据与X连锁低磷血症患者的数据相结合,以了解药代动力学和药代动力学/药效学特征以及肿瘤诱导性骨软化症特有的协变量。使用最终模型进行了药代动力学和药代动力学/药效学模拟,以支持成人用药剂量建议,并外推至儿科患者。布罗苏单抗的药代动力学采用一室模型进行描述,该模型具有一阶吸收,体重是一个重要的协变量。药代动力学/药效学关系是通过一个西格玛Emax模型来描述的,基线成纤维细胞生长因子23对基线空腹血清磷酸盐和布索单抗反应效力以及肿瘤诱导的骨软化症疾病状态具有重要的协变量,导致反应斜率陡峭;然而,这些协变量并不具有临床意义。模拟实验表明,在儿科患者中,起始剂量为0.3和0.4 mg/kg,每2周一次的布罗苏单抗稳态治疗可使≥30%的患者达到正常血清磷酸盐水平,而高磷酸盐血症的风险相对较低 (
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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 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-22 DOI: 10.1002/cpt.3463
Ashish Sharma, Islam R Younis, Jitendra Kanodia, Vaishali Sahasrabudhe

The IQ CPLG Organ Impairment WG conducted a survey to understand how various IQ member companies develop dosing recommendations for patients with renal impairment. Eighteen IQ member companies participated in the survey. The survey results were summarized by the working group in light of the regulatory renal impairment guidance documents as well as recent publications from the pharmaceutical industry and nephrology community. There were two important learnings from the survey: (i) pharmaceutical companies do not use a consistent methodology to assess renal function in their drug development programs. (ii) there has been significant improvement in predicting how kidney function affects drug pharmacokinetics (PK) and thus dose recommendations. Applying model-based methods such as population PK, physiologically-based PK (PBPK), and virtual controls has enabled earlier prediction of how kidney function influences PK, leading to the participation of more patients with impaired kidney function in Phase 2 and 3 trials.

IQ CPLG 器官损伤工作组进行了一项调查,以了解各 IQ 成员公司如何为肾功能损伤患者制定用药建议。18 家 IQ 成员公司参与了调查。工作组根据监管部门的肾功能损害指导文件以及制药行业和肾病学界最近的出版物对调查结果进行了总结。调查有两个重要发现:(i) 制药公司在药物开发项目中没有使用统一的方法来评估肾功能。(ii) 在预测肾功能如何影响药物药代动力学 (PK) 以及剂量建议方面已经取得了重大进展。应用基于模型的方法,如群体 PK、基于生理的 PK (PBPK) 和虚拟对照,可以更早地预测肾功能对 PK 的影响,从而让更多肾功能受损的患者参与 2 期和 3 期试验。
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引用次数: 0
First-in-Human Evaluation of Safety, Pharmacokinetics and Muscle Glycogen Lowering of a Novel Glycogen Synthase 1 Inhibitor for the Treatment of Pompe Disease. 首次对治疗庞贝氏症的新型糖原合成酶 1 抑制剂的安全性、药代动力学和肌肉糖原降低作用进行人体评估
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-22 DOI: 10.1002/cpt.3470
Julie C Ullman, Ryan A Dick, Daniela Linzner, Todd Minga, Samnang Tep, Terrence F Satterfield, Yannan Xi, David T Beattie, Tonya Marmon, Joel M Neutel, Bernard Chung, Janet M Leeds, Sarah B Noonberg, Eric M Green, Harold S Bernstein

Pompe disease is a rare glycogen storage disease caused by mutations in the enzyme acid α-glucosidase (GAA) resulting in pathological accumulation of glycogen in muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA is currently the sole treatment option for patients with Pompe disease. ERT burdens patients with frequent intravenous infusions while insufficiently halting disease progression due to incomplete ERT skeletal muscle distribution. Glycogen synthase 1 (GYS1) has been proposed as a substrate reduction therapy (SRT) target for Pompe disease. Here, we report results from the first-in-human study of the orally available GYS1 inhibitor MZE001 in healthy subjects. In 88 participants, MZE001 was well-tolerated up to a single dose of 480 mg BID and multiple doses of 720 mg BID for 10 days. Noncompartmental analysis determined that the half-life and Ctrough concentrations of MZE001 could provide efficacious exposures with once or twice daily oral dosing. Change from baseline of peripheral blood mononuclear cell (PBMC) glycogen, which correlated with muscle glycogen levels in preclinical models, was significantly reduced dose-dependently following 10 days of MZE001 treatment in healthy subjects. A muscle biopsy sub-study demonstrated that 10 days of MZE001 (480 mg BID) dosing safely and substantially lowered muscle glycogen stores in healthy adults. This correlated with the PBMC exposure response and supports the use of PBMC glycogen reduction as a surrogate for muscle response, and MZE001 potential for development as the first oral substrate reduction therapy for patients with Pompe disease.

庞贝氏症是一种罕见的糖原贮积病,是由于酸性α-葡萄糖苷酶(GAA)发生突变,导致糖原在肌肉组织中病理性蓄积,从而引起进行性乏力和呼吸功能障碍。使用 GAA 的酶替代疗法(ERT)是目前治疗庞贝病患者的唯一方法。由于ERT骨骼肌分布不完全,ERT不能充分阻止疾病的进展。糖原合成酶 1 (GYS1) 已被提出作为庞贝氏症的底物还原疗法 (SRT) 靶点。在此,我们报告了在健康受试者中首次进行的口服 GYS1 抑制剂 MZE001 的人体研究结果。在 88 名参与者中,MZE001 的耐受性良好,单次剂量为 480 毫克,每日一次,多次剂量为 720 毫克,每日一次,连续 10 天。非室分析表明,MZE001的半衰期和Ctrough浓度可以提供每天口服一次或两次的有效暴露量。在临床前模型中,外周血单核细胞(PBMC)糖原与肌糖原水平相关,而在健康受试者中,MZE001治疗10天后,外周血单核细胞(PBMC)糖原与基线的变化呈剂量依赖性显著降低。肌肉活检子研究表明,健康成年人服用10天的MZE001(480毫克,每日两次)可安全地大幅降低肌糖原含量。这与 PBMC 暴露反应相关,支持使用 PBMC 糖原减少作为肌肉反应的替代物,并支持将 MZE001 开发为庞贝病患者的第一种口服底物减少疗法。
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引用次数: 0
Risk of Opioid Overdose Associated with Concomitant Use of Methadone and Statins. 同时使用美沙酮和他汀类药物导致阿片类药物过量的风险。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-21 DOI: 10.1002/cpt.3479
Cheng Chen, Todd A Miano, Colleen M Brensinger, Charles E Leonard, Warren B Bilker, Sean Hennessy

Methadone has a high potential for risky drug-drug interactions that can lead to opioid overdose, yet evidence on the magnitude of this risk remains limited. Since methadone is transported via P-glycoprotein (P-gp), the use of statins that inhibit P-gp may elevate methadone plasma concentrations, potentially leading to opioid overdose. We explored this hypothesis by examining whether concomitant use of methadone and P-gp-inhibiting statins was associated with opioid overdose. Using Medicaid claims data from 2003 to 2020, we conducted a cohort study among new concomitant users of methadone and statins. We compared overdose rates among individuals exposed to P-gp-inhibiting statins (simvastatin, atorvastatin, or lovastatin) vs. those exposed to rosuvastatin (negative control), adjusting for baseline covariates. We identified 69,263 individuals newly exposed to methadone and a statin of interest; the overall incidence rate of opioid overdose was 26.0 per 1,000 person-years. Adjusted hazard ratios (HRs) for methadone + P-gp-inhibiting statins consistently showed no association, ranging from 0.76 (95% CI = 0.48-1.22) for atorvastatin to 0.78 (95% CI = 0.50-1.22) for simvastatin, compared with methadone + rosuvastatin. Similar results were observed in sensitivity analysis that treated all P-gp-inhibiting statins as a single exposure group, as well as analyses stratified by baseline diagnosis of opioid use disorder or overdose, the duration of baseline methadone use, and calendar year intervals. Our findings suggest that concomitant use of methadone with simvastatin, atorvastatin, or lovastatin is not associated with the risk of opioid overdose compared to concomitant use of methadone and rosuvastatin.

美沙酮极有可能发生危险的药物相互作用,从而导致阿片类药物过量,但有关这种风险大小的证据仍然有限。由于美沙酮通过P-糖蛋白(P-gp)转运,使用抑制P-gp的他汀类药物可能会提高美沙酮的血浆浓度,从而可能导致阿片类药物过量。我们通过研究同时使用美沙酮和抑制 P-gp 的他汀类药物是否与阿片类药物过量有关来探讨这一假设。利用 2003 年至 2020 年的医疗补助报销数据,我们对同时使用美沙酮和他汀类药物的新用户进行了一项队列研究。我们比较了暴露于 P-gp 抑制他汀类药物(辛伐他汀、阿托伐他汀或洛伐他汀)与暴露于罗伐他汀(阴性对照)的患者的过量用药率,并对基线协变量进行了调整。我们确定了 69,263 名新接触美沙酮和相关他汀类药物的患者;阿片类药物过量的总体发病率为每千人年 26.0 例。与美沙酮+罗苏伐他汀相比,美沙酮+P-gp抑制他汀的调整后危险比(HRs)始终显示没有关联,阿托伐他汀为0.76(95% CI = 0.48-1.22),辛伐他汀为0.78(95% CI = 0.50-1.22)。将所有 P-gp 抑制他汀类药物作为单一暴露组进行的敏感性分析,以及根据阿片类药物使用障碍或过量的基线诊断、美沙酮基线使用时间和日历年间隔进行的分层分析也观察到了类似的结果。我们的研究结果表明,与同时使用美沙酮和罗伐他汀相比,同时使用美沙酮和辛伐他汀、阿托伐他汀或洛伐他汀与阿片类药物过量的风险无关。
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引用次数: 0
Collaborative Real-World Evidence Among Regulators: Lessons and Perspectives. 监管者之间的合作实证:经验与展望。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-21 DOI: 10.1002/cpt.3457
Andrew E Beck, Melissa Kampman, Cindy Huynh, Craig Simon, Kelly Plueschke, Catherine Cohet, Patrice Verpillat, Kelly Robinson, Peter Arlett

The International Coalition of Medicines Regulatory Authorities (ICMRA), comprising 38 global medicines regulatory authorities, collaborates on shared challenges, notably during the COVID-19 pandemic. This article focuses on the ICMRA COVID-19 Real-World Evidence (RWE) and Observational Studies Working Group. The Working Group aimed to address challenges related to RWE and observational studies during the pandemic, resulting in impactful studies and ICMRA statements on international collaboration for RWE and COVID-19 vaccine safety. Reflecting on 3 years of collaboration, the Working Group surveyed members for insights, and recommendations were formulated to enhance research preparedness, collaboration, and response to future public health emergencies. The lessons learned highlight the importance of global collaborations, governance structures for rapid decision-making, and effective utilization of existing networks. Recommendations include the establishment of an international governance structure, a "coalition of the willing" for swift research collaboration, dedicated sub-groups, periodic workshops, common protocols, joint timelines, and data model templates, leveraging existing infrastructure, and strengthening outreach for transparency and engagement. The Working Group envisions repurposing into an RWE strategic and operational entity, contributing to global public health emergency response mechanisms. In conclusion, the Working Group's success lies in effective communication, collaborative research, and leveraging existing infrastructure, with ongoing contributions to global emergency response mechanisms.

由全球 38 个药品监管机构组成的国际药品监管机构联盟 (ICMRA) 就共同面临的挑战开展合作,尤其是在 COVID-19 大流行期间。本文重点介绍 ICMRA COVID-19 真实世界证据 (RWE) 和观察研究工作组。该工作组旨在应对大流行期间与 RWE 和观察研究相关的挑战,开展了具有影响力的研究,并发表了 ICMRA 关于 RWE 和 COVID-19 疫苗安全性国际合作的声明。在对 3 年的合作进行反思后,工作组对成员进行了调查,以了解他们的见解,并提出了加强研究准备、合作和应对未来公共卫生突发事件的建议。这些经验教训强调了全球合作、快速决策治理结构和有效利用现有网络的重要性。建议包括建立国际管理结构、迅速开展研究合作的 "意愿联盟"、专门的分组、定期研讨会、共同协议、联合时间表和数据模型模板、利用现有基础设施以及加强外联以提高透明度和参与度。工作组设想将其调整为一个 RWE 战略和业务实体,为全球公共卫生应急机制做出贡献。总之,工作组的成功在于有效沟通、合作研究和利用现有基础设施,并不断为全球应急机制做出贡献。
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引用次数: 0
Effect of Dapagliflozin on Measured vs. Panel-Estimated Glomerular Filtration Rate. 达帕格列净对实测肾小球滤过率与专家小组估算肾小球滤过率的影响。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-21 DOI: 10.1002/cpt.3480
Esben Iversen, Line Juel Nielsen, Viktor Rotbain Curovic, Anne Byriel Walls, Mie Klessen Eickhoff, Marie Frimodt-Møller, Frederik Persson, Peter Rossing, Morten Baltzer Houlind

Sodium-glucose cotransporter 2 (SGLT2) inhibitors can cause a reversible decline in glomerular filtration rate (GFR), which may influence dosing recommendations for renally excreted medications. In practice, GFR is typically estimated by serum creatinine concentration, but creatinine may not be a reliable indicator of GFR decline in the setting of SGLT2 inhibitor use. Alternative filtration markers such as cystatin C, β-trace protein (BTP), and β2-microglobulin (B2M) may be more appropriate, but little is known about how these markers are affected by SGLT2 inhibitor use. Therefore, we determined creatinine, cystatin C, BTP, and B2M concentration in a crossover study of 35 people with type 2 diabetes receiving 12 weeks of dapagliflozin treatment or placebo. Estimated GFR (eGFR) based on creatinine (eGFRcre), cystatin C (eGFRcys), their combination (eGFRcomb), or a panel of all four markers (eGFRpanel) was compared with measured GFR (mGFR) based on plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid (51Cr-EDTA). Dapagliflozin treatment was associated with a significant decrease in mGFR (-9 mL/min/1.73 m2, P < 0.001) but not a corresponding increase in concentration of any filtration marker. No eGFR equation accurately predicted change in mGFR between treatment periods, but eGFRcomb and eGFRpanel yielded the highest overall accuracy relative to mGFR across both treatment periods. These findings highlight the stability in performance gained by combining multiple filtration markers but suggest that eGFR in general is not an ideal metric for assessing short-term GFR decline in people initiating SGLT2 inhibitor therapy.

钠-葡萄糖共转运体 2(SGLT2)抑制剂可导致肾小球滤过率(GFR)可逆性下降,这可能会影响肾脏排泄药物的用药建议。实际上,肾小球滤过率通常是通过血清肌酐浓度来估算的,但在使用 SGLT2 抑制剂的情况下,肌酐可能并不是肾小球滤过率下降的可靠指标。胱抑素 C、β-痕量蛋白(BTP)和β2-微球蛋白(B2M)等其他滤过标志物可能更合适,但人们对这些标志物如何受 SGLT2 抑制剂使用的影响知之甚少。因此,我们在一项交叉研究中测定了肌酐、胱抑素 C、BTP 和 B2M 的浓度,研究对象是接受 12 周达帕格列酮治疗或安慰剂治疗的 35 名 2 型糖尿病患者。根据肌酐(eGFRcre)、胱抑素 C(eGFRcys)、它们的组合(eGFRcomb)或所有四种标记物的组合(eGFRpanel)估算的 GFR(eGFR)与根据铬-51 标记的乙二胺四乙酸(51Cr-EDTA)的血浆清除率测量的 GFR(mGFR)进行了比较。达帕格列净治疗与 mGFR 的显著下降有关(-9 mL/min/1.73 m2,P
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Clinical Pharmacology & Therapeutics
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