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Quantifying effects of comorbidities and genetics on cannabinoid exposure in the elderly

量化合并症和遗传学对老年人大麻素暴露的影响

基本信息

批准号：
10672380
负责人：
Zhu Zhou
金额：
$ 19.78万
依托单位：
YORK COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672380
关键词：
Adult Adverse drug event Affect Age Aging American Automobile Driving Benefits and Risks Blood flow CYP2C19 gene CYP2C9 gene CYP3A4 gene Cannabidiol Cannabinoids Cannabis Cannabis sativa plant Caring Characteristics Child Clinical Research Complex Computer software Conduct Clinical Trials Cytochrome P450 Data Databases Development Dose Elderly Enzymes Exposure to Foundations Future Genetic Genetic Polymorphism Goals Health Health Professional Hemp Hepatic Hepatic Mass Herbal supplement Impairment In Vitro Individual Industry Ingestion Inhalation Knowledge Legal Link Liver Liver diseases Marijuana Mediating Medical Medical Marijuana Mental Depression Metabolic Biotransformation Metabolism Minor Modeling Oils Oral Pain Patients Pharmaceutical Preparations Phenotype Physiological Plasma Population Process Public Health Regimen Renal function Reporting Research Project Grants Risk Assessment Safety Severity of illness Sleeplessness Smoke Special Population Statutes and Laws THC concentration THC exposure Tetrahydrocannabinol Variant Xenobiotics adverse event risk age effect age related aged comorbidity enzyme activity genetic variant healthy aging human old age (65+)in silico interest marijuana use marijuana user models and simulation novel older patient pharmacokinetic model trend young adult

项目摘要

Project summary/abstract Americans ≥65 years represent a growing segment of the US population who use cannabis for multiple ailments, increasing about two-fold from 2015 to 2018. Despite these trends, knowledge about how the aging process combined with comorbidities or genetic polymorphisms in drug metabolizing enzymes alter the safety of cannabis remains limited. This knowledge gap is particularly worrisome given nearly all 50 states have passed some legislation allowing legal medical cannabis use and that the elderly are more vulnerable to adverse drug events. The non-psychoactive cannabidiol (CBD) and psychoactive ∆-9-tetrahydrocannabinol (THC) are the most extensively studied cannabinoids in cannabis. CBD has been the top-selling herbal supplement ingredient in the US natural channel since 2018. CBD received particular interest from the elderly suffering comorbidities who are poorly managed with current treatments. CBD is eliminated from the body mainly by hepatic cytochrome P450 (CYP)-mediated metabolism (CYP2C19, CYP3A). Mean THC concentration in cannabis-related products was reported to increase 2-fold from 2008 to 2017. THC is eliminated mainly by hepatic CYP-mediated metabolism, primarily by CYP2C9, with a minor contribution by CYP3A. Biotransformation activity generally tends to slow with age due to decreased blood flow and reduced liver mass. Both CYP2C19 and CYP2C9 harbor multiple reduced function genetic variants that could further reduce the safety of CBD and THC. Therefore, the elderly with hepatic impairment or carrying such genetic variants may be at heightened risk for adverse events from CBD and THC. Collectively, there is an urgent and critical need to understand how comorbidities such as hepatic impairment, along with select CYP variants, affect CBD and THC disposition in the elderly. Because conducting clinical trials in the elderly can be challenging, model-based approaches such as physiologically-based pharmacokinetic (PBPK) modeling and simulation can be used to project systemic exposure to CBD and THC. The objective of this project is to incorporate age-related physiological changes, hepatic impairment, and select CYP genetic variants, as well as oral or inhaled CBD- and THC-specific characteristics, into novel PBPK models to predict CBD and THC disposition in hepatic-impaired elderly patients (65-98 years) and assess the combined effects of age and genetic CYP polymorphisms on CBD and THC exposure. We will (1) quantify the effects of age on oral and inhaled CBD and THC disposition and (2) develop PBPK models to predict both oral and inhaled CBD and THC exposure in elderly patients with hepatic impairment and (3) assess the impact of select CYP genetic variants on oral and inhaled CBD and THC exposure in the elderly. Results from this project are expected to provide critical and timely data to inform consumers and health care professionals about the safety linked to CBD and THC use among the elderly with and without hepatic impairment or select CYP genetic variants. Importantly, results will lay the foundation for future benefit/risk assessment of the complex natural cannabinoid mixture (cannabis/marijuana/hemp) in this special population.

项目概要/摘要 65 岁以上的美国人在美国人口中使用大麻治疗多种疾病的比例不断增长，从 2015 年到 2018 年，这一数字增加了约两倍。尽管有这些趋势，但关于衰老过程的知识与药物代谢酶的合并症或遗传多态性相结合会改变大麻的安全性仍然有限。鉴于几乎所有 50 个州都通过了一些立法允许合法使用医用大麻，老年人更容易受到药物不良事件的影响。非精神活性大麻二酚 (CBD) 和精神活性 Δ-9-四氢大麻酚 (THC) 是最广泛研究了大麻中的大麻素。 CBD 一直是最畅销的草药补充剂成分自 2018 年以来，美国自然通道。CBD 受到患有合并症的老年人的特别关注，他们目前的治疗方法管理不善。 CBD主要通过肝细胞色素P450从体内消除 (CYP) 介导的代谢（CYP2C19、CYP3A）。大麻相关产品的平均 THC 浓度为据报道，从 2008 年到 2017 年增加了 2 倍。 THC 主要通过肝脏 CYP 介导的代谢消除，主要由 CYP2C9 贡献，CYP3A 贡献较小。生物转化活性通常趋于减慢由于血流量减少和肝脏质量减少而导致年龄增长。 CYP2C19 和 CYP2C9 均具有多重减少功能基因变异可能进一步降低 CBD 和 THC 的安全性。因此，患有肝病的老年人损伤或携带此类遗传变异可能会面临 CBD 和 THC 不良事件的更高风险。总的来说，迫切需要了解肝功能损害等合并症、与选定的 CYP 变体一起影响老年人的 CBD 和 THC 处置。由于在老年人中进行临床试验可能具有挑战性，因此基于模型的方法，例如基于生理学的药代动力学 (PBPK) 建模和模拟可用于预测系统性接触 CBD 和 THC。该项目的目标是纳入与年龄相关的生理变化，肝功能损害，并选择 CYP 基因变异，以及口服或吸入 CBD 和 THC 特异性特征，融入新型 PBPK 模型中，以预测肝受损老年患者的 CBD 和 THC 分布（65-98岁）并评估年龄和遗传CYP多态性对CBD和THC的综合影响接触。我们将 (1) 量化年龄对口服和吸入 CBD 和 THC 处置的影响，以及 (2) 开发 PBPK 模型预测老年肝功能损害患者口服和吸入 CBD 和 THC 的暴露 (3) 评估特定 CYP 基因变异对口服和吸入 CBD 和 THC 暴露的影响老年。该项目的结果预计将提供关键和及时的数据，以告知消费者和健康护理专业人员了解患有或不患有肝病的老年人使用 CBD 和 THC 的安全性损伤或选择 CYP 遗传变异。重要的是，结果将为未来的收益/风险奠定基础评估这一特殊人群中复杂的天然大麻素混合物（大麻/大麻/大麻）。