LB-008 - GENOTYPE-SPECIFIC SAFTEY PROFILES AND PHARMACOKINETICS OF CANNABIDIOL IN HEALTHY SUBJECTS

J. Etkins¹, G. So¹, K. McClara¹, J. Lu², D. Gisch¹, S. Koyama¹, Z. Desta³, M. Eadon⁴; ¹Indiana University School of Medicine, Indiana, IN, USA, ²Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, United States, ³Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis,IN, US, ⁴Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Cannabidiol use is increasing amongst Americans due to its widespread availability over the counter and via prescription. Less is known regarding safety, as a common reported side effect is diarrhea. Cannabidiol is metabolized by multiple polymorphic enzymes including CYP3A and CYP2C19. We aim to evaluate the genotype-specific adverse events of cannabidiol and 7-OH cannabidiol.

Methods: We completed an open-label, fixed sequence, single-center study of cannabidiol (EPIDIOLEX®; Greenwich Biosciences, Carlsbad, CA) in 34 healthy subjects. Patients first received a single dose of cannabidiol 5 mg/kg orally with serial blood draws to determine pharmacokinetics. Later, subjects were titrated to cannabidiol 5 mg/kg twice daily for 14 days to reach steady state. The concentration of cannabidiol was measured using a highly sensitive UPLC instrument coupled with QTRAP 6500+ MS/MS. Genotypes were assessed for CYP3A5 and CYP2C19. Pharmacokinetic parameters were calculated by noncompartmental analysis using Phoenix® WinNonlin® version 8.4 (Certara L.P. (Pharsight), Princeton, NJ). The data became available and were analyzed on 11/12/2024.

Results: In the entire cohort (n=34), a greater incidence of diarrhea was appreciated in individuals with both CYP3A5 poor metabolism and CYP2C19 intermediate/ normal metabolism (8 of 15, 54%) compared to individuals with either CYP3A5 expression or CYP2C19 ultrarapid/ rapid metabolism (3 of 19, 16%, p=0.03).

For the first 16 subjects with pharmacokinetics data, the mean maximum concentration (Cmax) of cannabidiol and 7-OH cannabidiol for the single dose was 277 ± 211.9 and 92.6 ± 120.3 ng/mL respectively. The mean Cmax values for cannabidiol and 7-OH cannabidiol at steady state were 412.8 ± 255 and 133.7 ± 130 ng/mL.

The single dose mean area under the curve (AUC0-∞) for cannabidiol and 7-OH cannabidiol were 2040 ± 984.5 and 1129.2 ± 1961.5 ng*h/mL, respectively. The mean steady state (AUC0−τ) value of cannabidiol and 7-OH cannabidiol were 2031 ± 876 and 838.9 ± 726.8ng*h/mL.

No significant difference in Cmax was observed based on CYP3A5 and CYP2C19 genotype in the 16 analyzed subjects.

Conclusion: This study is the first report to demonstrate the increased incidence of cannabidiol-related diarrhea in individuals without either CYP3A5 expression or CYP2C19 rapid metabolism