Objective: To evaluate the pharmacokinetics of a purified oral cannabidiol (CBD) capsule administered with and without food in adults with refractory epilepsy. Methods: Adult patients who were prescribed CBD for seizures, had localization-related intractable epilepsy with ≥4 seizures per month, and qualified for Minnesota cannabis were enrolled. A single dose of 99% pure CBD capsules was taken under both fasting (no breakfast) and fed (high fat 840-860 calorie) conditions. Blood sampling for CBD plasma concentrations was performed under each condition between 0 and 72 hours post-dose and measured by a validated liquid chormatography-mass spectometry assay. CBD pharmacokinetic profiles including maximum concentration (Cmax), area-under-the-curve from zero to infinity (AUC0-∞), and time-to-maximum concentration (Tmax) were calculated. The confidence intervals (CIs) for log-transformed Cmax and AUC0-∞ ratios between fed and fasting states were calculated. Seizure and adverse events information was collected. Results: Eight patients completed the study. On average Cmax was 14 times and AUC0-∞ 4 times higher in the fed state. The 90% CI for the ratio of fed versus fast conditions for Cmax and AUC0-∞ were 7.47-31.86 and 3.42-7.82, respectively. No sequence or period effect for Cmax and AUC0-∞ was observed. No adverse events were reported. Significance: Administering CBD as a capsule rather than a liquid allows for more precise determination of pharmacokinetics parameters and is more representative of CBD swallowed products. The fat content of a meal can lead to significant increases in Cmax and AUC0-∞ and can account for variability in bioavailability and overall drug exposure within patients with oral products.
Bibliographical noteFunding Information:
Angela K Birnbaum reports grants from the Epilepsy Foundation, National Institutes of Health, Superunus Pharmaceuticals, and Veloxis Pharmaceutics during the conduct of the study. She also has a royalty agreement for intravenous carbamazepine with Lundbeck. Susan E Marino reports grants from the Epilepsy Foundation, National Institutes of Health, Superunus Pharmaceuticals, and Veloxis Pharmaceutics during the conduct of the study. She and Rory P Remmel have a royalty agreement for intravenous topiramate with Ligand Pharmaceuticals. Ilo E Leppik reports grants from the Epilepsy Foundation, National Institutes of Health, and Superunus Pharmaceuticals during the conduct of the study. Christopher M Barkley, Michaela J Roslawski, Mary Gramling‐Aden and Ashwin Karanam have no conflicts to declare. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
The study was funded by the Patricia L Nangle Fund through the Epilepsy Foundation, and the MacMillan Innovative Epilepsy Research and Education Fund. We wish to thank the staff, patients, and physicians at University of Minnesota Physicians/MINCEP Epilepsy Care for their help with this study. We are also thankful to Vireo for aiding with the cost of CBD for patients in our study.
Wiley Periodicals, Inc. © 2019 International League Against Epilepsy