A study on CYP2C9 polymorphism in Puerto Rican Alzheimer's Patients and its role in the Pharmacokinetics of ∆-9-tetrahydrocanna-binol

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects over 55 million people worldwide. Individuals with AD are often prescribed multiple medications to manage comorbidities, many of which are metabolized by enzymes from the cytochrome P450 (CYP). CYP2C9 is expressed by the CYP2C9 gene. The highly polymorphic gene is grouped into phenotypes such as poor, intermediate, normal, and ultra-rapid metabolizers that influence the pharmacokinetics (PK) of drugs and their metabolites. Among humans, CYP2C9 is one of the most essential enzymes for metabolizing drugs, including delta-9-tetrahydrocannabinol (THC). The enzyme converts THC into its active metabolite 11-hydroxy-delta-9-THC (OH-THC). IGC-AD1 is a formulation with two active pharmaceutical ingredients, delta-9-THC and melatonin. The Phase 1, multiple ascending dose (MAD) trial, was conducted on a Puerto Rican population. The participant population in the trial (N=13) was 69.2% female and 30.8% male, with an average age of 80.18 (SD+/- 6.22). We report on the effect of CYP2C9 polymorphisms on the pharmacokinetics (PK) of THC and its active metabolite in AD patients from a Phase 1 trial. Using a Mass ARRAY Analyzer 4 Instrument (Invitae Inc.), we determined the following CYP2C9 alleles: *2, *3, *4, *5, *6, *8, *11, *13, *15, and found that 60% of participants (N=6) were carriers of at least one polymorphism including 1*/2* and 1*/3*. The participants with intermediate metabolizers (*1/*3 and *1/*2) showed an increased half-life of THC and OH-THC with major differences between the two intermediate metabolizer groups *1/*3 and *1/*2. In the trial more females were noted to be intermediate metabolizers than males. As polymorphisms of CYP2C9 affect the PK of THC and its metabolite, larger studies are needed to establish PK baselines for polymorphisms of CYP2C9. In the meantime, it is recommended that researchers exercise caution while dosing AD patients with THC.