Abstracts

Rationale: Cannabidiol CBD is highly lipophilic and evidence exists for a food effect at lower doses (Stott et. al., 2013). Thus variability in pharmacokinetics and seizure control in patients treated with CBD may be observable if doses are not always taken under consistent dietary constraints. A high-grade product CBD capsule is available in Minnesota and being taken by patients. Our objective was to evaluate CBD pharmacokinetics after administration of CBD capsules with and without food so that clinicians can advise how best to take CBD. Methods: The pharmacokinetics of CBD was studied in adult patients with refractory epilepsy under two conditions: fed and fasting. Adult patients who had localization related intractable epilepsy by EEG and semiology, occurrence of four or more seizures per month, and a minimum of care of six months at UMP-MINCEP Epilepsy Care Clinic were enrolled. Excluded were women of childbearing potential not practicing contraception, history of recent status epilepticus, unable to personally give informed consent, or have a criminal or abuse record (Minnesota law restriction). Each patient took the CBD that was prescribed by the dispensary under both fasting (no breakfast) and fed (high fat 840-860 calorie egg wrap with sausage or bacon) with at least one week between doses so served as their own control. Patients used the “violet” MN formulation containing 100 mg of CBD encased in a vegetable cellulose capsule with a food-grade coconut oil excipient. Blood samples were taken 0, 0.5, 1, 2, 2.5, 3.5, 4, 5, 6, 24, 48, and 72 hours after dose administration. We used a validated assay in our laboratory measuring thirteen cannabinoid compounds including CBD, THC, and metabolites. CBD and cannabidioloic acid have a limit of quantification of 50 and 100 pg/ml, respectively with accuracy of 97-102% and intra- and inter-assay precision of < 5%. CBD pharmacokinetic profiles and bioequivalence confidence intervals (CI) for the ratios of fasting vs fed Cmax and AUC0-inf were calculated using Phoenix WinNonlin software (Ceratara). Repeated measures ANOVA was used to identify effect of period and sequence on Cmax and AUC0-inf. Results: Five male patients (aged 25-78 years) were prescribed CBD doses of 200 or 300 mg providing eight pharmacokinetic profiles and geometric means. CBD had comparable half-lives in the fed vs fasting groups (30 vs 24 hours) and comparable elimination rate constants (0.023 vs 0.029 hr-1). CBD fasting vs fed dose normalized Cmax was 0.028 vs 0.355 ng/mL/mg respectively, while the dose normalized AUC0-inf was 0.44 vs 2.92 hr*ng/mL/mg, respectively. There was no sequence or period effect for Cmax and AUC0-inf; however, there was a significant effect between the fed and fasting CBD state for Cmax and AUC0-inf (p=0.025 and p=0.008) (90% CI 1.62-5.81 CBD Cmax; 1.69-3.21 AUC0-inf). Individual ratios (fed/fast) of AUC0-inf (range 2.5-13.1) was lower than in Cmax (2.1-54.7). Conclusions: These results indicate a significant food effect for CBD at higher doses than tested previously with a combination formulation. Administering CBD with a high fat meal led to significantly higher Cmax and higher AUC0-inf (i.e. higher exposure). CBD exposure could vary if administered with or without meals. References:Stott CG, White L, Wright S, Wilbraham D, Guy GW. A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray. Eur J Clin Pharmacol. 2013 Apr;69(4):825-34. doi: 10.1007/s00228-012-1393-4. Funding: Funded by the Epilepsy Foundation and the Patricia L Nangle Fund