Pharmacokinetic Variability of Oral Cannabidiol and Its Major Metabolites after Short-Term High-Dose Exposure in Healthy Subjects

Abstract

<b><i>Introduction:</i></b> Cannabidiol (CBD) is a widely utilized nonpsychoactive cannabinoid available as a prescriptive drug treatment and over-the-counter supplement. In humans, CBD is metabolized and forms the major active metabolite 7-hydroxy-cannabidiol (7-OH-CBD), which is further metabolized to 7-carboxy-cannabidiol (7-COOH-CBD). In the current study, plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD were measured, and the potential influences of sex, race, and body mass index (BMI) on the pharmacokinetic variability were assessed. <b><i>Methods:</i></b> Blood samples from a previously conducted CBD drug interaction study in healthy volunteers (<i>n</i> = 12) were utilized. The subjects received orally administered CBD (Epiodiolex<sup>®</sup>), 750 mg twice daily for 3 days and a single dose on the 4th day. Nine plasma samples were collected, and plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD were analyzed by LC-MS/MS. Peak plasma concentration (C<sub>max</sub>), time to C<sub>max</sub> (T<sub>max</sub>), area under the curve (AUC), and metabolite‐to‐parent drug exposure ratios (MPR) were calculated. Statistical analysis was performed to determine the correlations of C<sub>max</sub>, AUC, and MPR of CBD, 7-OH-CBD, and 7-COOH-CBD in different sex, race, BMI, and body weight. <b><i>Results:</i></b> For CBD, the mean C<sub>max</sub> was 389.17 ± 153.23 ng/mL, and the mean AUC was 1,542.19 ± 488.04 ng/mL*h. For 7-OH-CBD, the mean C<sub>max</sub> was 81.35 ± 36.64 ng/mL, the mean AUC was 364.70 ± 105.59 ng/mL*h, and the mean MPR was 0.25 ± 0.07. For 7-COOH-CBD, the mean C<sub>max</sub> was 1,717.33 ± 769.22 ng/mL, the mean AUC was 9,888.42 ± 3,961.47 ng/mL*h, and the mean MPR was 7.11 ± 3.48. For 7-COOH-CBD, a 2.25-fold higher C<sub>max</sub> was observed in female subjects (<i>p</i> = 0.0155) and a 1.97-fold higher AUC for female subjects (<i>p</i> = 0.0285) with the normalization of body weight. A significant linearity (<i>p</i> = 0.0135) of 7-OH-CBD AUC with body weight in females was observed. No significant differences were identified in C<sub>max</sub>, AUC, and PMR with race and BMI. <b><i>Conclusion:</i></b> Observed differences in sex were in agreement with previously reported findings. A larger population pharmacokinetics study is warranted to validate the observed higher C<sub>max</sub> and AUC in females and significant linearity with body weight in females from the current study.