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

Award Number: R16GM146679
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $201,485 )
2025	2025	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	94-20 GUY R BREWER BLVD	JAMAICA	NY	11451	QUEENS	USA	Biomedical Research and Research Training	000	4	8/19/2025	NON-COMPETING CONTINUATION	$201,485
														Subtotal = $201,485

Issue Date FY: 2024 ( Subtotal = $199,599 )
2024	2024	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	94-20 GUY R BREWER BLVD	JAMAICA	NY	11451	QUEENS	USA	Biomedical Research and Research Training	000	3	7/5/2024	NON-COMPETING CONTINUATION	$199,599
														Subtotal = $199,599

Issue Date FY: 2023 ( Subtotal = $197,777 )
2023	2023	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	94-20 GUY R BREWER BLVD	JAMAICA	NY	11451	QUEENS	USA	Biomedical Research and Research Training	000	2	8/24/2023	NON-COMPETING CONTINUATION	$197,777
														Subtotal = $197,777

Issue Date FY: 2022 ( Subtotal = $195,750 )
2022	2022	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	94-20 GUY R BREWER BLVD	JAMAICA	NY	11451	QUEENS	USA	Biomedical Research and Research Training	000	1	7/27/2022	NEW	$195,750
														Subtotal = $195,750

Grand Total All Awards = $794,611

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

Award Number: R16GM146679

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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