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

项目概要/摘要 ≥65岁的美国人代表了越来越多的美国人口，他们使用大麻治疗多种疾病， 从2015年到2018年增加了两倍。尽管有这些趋势， 与药物代谢酶中的共病或遗传多态性相结合改变大麻的安全性 仍然有限。这种知识差距尤其令人担忧，因为几乎所有50个州都通过了一些 立法允许法律的医用大麻使用，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）和精神活性大麻-9-四氢大麻酚（THC）是最多的 广泛研究大麻中的大麻素。CBD一直是最畅销的草药补充成分， 自2018年以来，美国自然频道。CBD受到患有合并症的老年人的特别关注， 目前的治疗效果不佳。CBD主要通过肝细胞色素P450从体内排出 （CYP 2C 19、CYP 3A）介导的代谢。大麻相关产品中的THC平均浓度为 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， 主要是CYP 2C 9，CYP 3A的贡献较小。生物转化活性通常倾向于减慢， 由于血流量减少和肝脏质量减少而导致的衰老。CYP 2C 19和CYP 2C 9均具有多重降低 功能遗传变异，可以进一步降低CBD和THC的安全性。因此，老年肝病患者 损伤或携带这种遗传变异可能会增加CBD和THC不良事件的风险。 总的来说，迫切需要了解肝损害等合并症， 沿着选择性β-内酰胺酶变体，影响老年人的CBD和THC分布。 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， 基于生理学的药代动力学（PBPK）建模和模拟可用于设计系统的 接触CBD和THC。该项目的目标是将与年龄有关的生理变化， 肝损害，和选择性的遗传变异，以及口服或吸入CBD和THC特异性 特征，进入新的PBPK模型，以预测肝损害老年患者的CBD和THC分布 （65-98岁），并评估年龄和遗传多态性对CBD和THC的综合影响 exposure.我们将（1）量化年龄对口服和吸入CBD和THC处置的影响，（2）开发 PBPK模型预测老年肝损害患者口服和吸入CBD和THC暴露 和（3）评估选择的遗传变异对口服和吸入CBD和THC暴露的影响， 老人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 护理专业人员对与CBD和THC在有肝和无肝的老年人中使用相关的安全性进行了研究。 缺陷或选择性遗传变异。重要的是，结果将为未来的获益/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）。

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.