Cytochrome P450 2C9 polymorphism in Puerto Rican Alzheimer’s patients and its role in the pharmacokinetics of THC and Melatonin (IGC‐AD1), an investigational drug

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a complex and chronic neurodegenerative illness. The AD patients were on many medications to manage their symptoms. Cytochrome P450 2C9 (CYP2C9) is the main enzyme involved in the metabolism of many drugs, including tetrahydrocannabinol (THC), which converts THC into the active metabolite 11‐hydroxy‐delta‐9‐THC metabolite. Individuals who lack CYP2C9 activity will have an increased risk of side effects from the drugs. CYP2C9 phenotypes are graded into groups, including poor (PM), intermediate (IM), normal (NM), and ultra‐rapid (UM) metabolizing phenotypes. IGC‐AD1 has major active ingredients that contain THC and melatonin.MethodIn our FDA‐regulated Phase‐1 trial, we evaluated a pilot study on the CYP2C9 polymorphism and pharmacokinetics of THC in AD patients (n = 12) from the Puerto Rican (PR) population as a safety measure. Using the Mass ARRAY Analyzer 4 instrument (Invitae Inc., MAA4, Agena, San Diego, CA), we determined the following CYP2C9 alleles: *2,*3,*4,*5,*6,*8,*11,*13,*15. We also investigate how polymorphism affects THC PK in IGC‐AD1 patients.ResultIn a Phase I clinical trial, we found that 62% of participants (n = 8) are carriers of at least one polymorphism. One participant has a rare heterozygous CYP2C9*1/*11 polymorphism. The participants with intermediate metabolizers (*1/*3 and *1/*2 allele) showed an increased half‐life of THC and an increased cMAX of OH‐THC compared to normal metabolizers (*1/*1). Participants who were intermediate metabolizers with *1/*2 variance had a lower AUC for THC levels. Altered CYP2C9 will affect the PK of THC and its metabolites.ConclusionFuture studies should include a larger sample size of AD patients from PR and other regions, that will be allowing access to CYP2C9 genetic polymorphism in AD and understand the drug‐related adverse reactions associated with CYP2C9 genetic polymorphism. Polymorphism plays an important role in drug metabolism and should be considered as a part of dosing.