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

• 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
• 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

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.

项目摘要/摘要 美国人≥65岁代表了使用大麻进行多种疾病的美国人口中越来越多的部分， 从2015年到2018年增加了大约两倍。尽管有这些趋势，但知道衰老过程如何 结合合并症或药物代谢酶的遗传多态性改变了大麻的安全性 仍然有限。鉴于几乎所有50个州都通过了一些，这种知识差距尤其令人担忧 法律允许使用法律大麻的法规，而古老的人更容易受到不良毒品事件的影响。 非精神活性大麻二酚（CBD）和精神活性∆-9-四氢大麻酚（THC）是最多的 大麻中广泛研究大麻素。 CBD是最畅销的草药补品成分 自2018年以来，美国自然频道。CBD从遭受的合并症中获得了特别的兴趣 目前的治疗方法管理不佳。 CBD主要通过肝细胞色素P450从体内消除 （CYP）介导的代谢（CYP2C19，CYP3A）。大麻相关产品中的平均THC浓度为 据报道，从2008年到2017年增加了2倍。 cyp2c9的主要作用，CYP3A的贡献较小。生物转化活动通常会随着 由于血液流量降低和肝脏质量减少而导致的年龄。 CYP2C19和CYP2C9均减少了多重 功能遗传变异，可以进一步降低CBD和THC的安全性。因此，以肝的方式 损伤或携带这种遗传变异可能会导致CBD和THC不良事件的风险增加。 总体而言，迫切需要了解肝损害等合并症， 除了选择的CYP变体外，还会影响CBD和THC处置。 因为在古老的情况下进行临床试验可能会受到挑战，所以基于模型的方法，例如 基于生理的药代动力学（PBPK）建模和模拟可用于投影系统性 暴露于CBD和THC。该项目的目的是结合与年龄相关的身体变化， 肝损伤，选择CYP遗传变异，以及口服或掺入CBD和THC特异性 特征，进入新型的PBPK模型，以预测肝损伤患者中的CBD和THC处置 （65 - 98年）并评估年龄和遗传CYP多态性对CBD和THC的综合作用 接触。我们将（1）量化年龄对口服和遗传CBD和THC处置的影响，以及（2） PBPK模型可预测古老的肝损伤患者的口服和遗传CBD和THC暴露 （3）评估选择CYP遗传变异对口服和掺入CBD的影响 老年。预计该项目的结果将提供关键和及时的数据，以告知消费者和健康 护理专业人员关于与CBD和THC在肝中使用的安全性和THC使用相关的安全性 损伤或选择CYP遗传变异。重要的是，结果将为未来的利益/风险奠定基础 在此特殊人群中评估复杂的天然大麻素混合物（大麻/大麻/大麻）。

项目成果

Patient, industry, and regulatory perspective on antibody-drug conjugates dose optimization.

患者、行业和监管机构对抗体药物偶联物剂量优化的看法。

• DOI: 10.1111/cts.13759
• 发表时间: 2024
• 期刊: Clinical and translational science
• 作者: Hamed,Salaheldin;Li,Chunze;Liao,MichaelZ;Warwick,Lorna;Zhou,Zhu
• 通讯作者: Zhou,Zhu

Managing Drug-Drug Interactions in Older Adults.

管理老年人的药物相互作用。

• DOI: 10.1002/jcph.2299
• 发表时间: 2023
• 期刊: Journal of clinical pharmacology
• 影响因子: 2.9
• 作者: Zhou,Zhu;Slattum,PatriciaW;Ke,Alice;Zhang,Lei
• 通讯作者: Zhang,Lei