Cannabidiol and CES1 Interactions in Healthy Subjects

Phase 4

Completed

Conditions: Drug Interaction

Interventions: Drug: dl-Methylphenidate plus Cannabidiol
Drug: dl-Methylphenidate plus Cannabidiol Placebo solution

Registration Number: NCT04603391

Lead Sponsor: University of Florida

Brief Summary: The proposed study will assess the drug interaction potential between oral cannabidiol (Epidiolex®) and the carboxylesterase 1 (CES1) substrate methylphenidate (Ritalin®) in 12 healthy research subjects

Detailed Description: Cannabidiol (CBD) is a widely utilized nonpsychoactive cannabinoid available as an OTC supplement, a component of medical cannabis, and a prescriptive treatment of childhood epilepsies. In vitro studies suggest CBD may inhibit a number of drug-metabolizing enzymes, including carboxylesterase 1 (CES1). The aim of this study was to evaluate effect of CBD on the disposition of the CES1 substrate methylphenidate (MPH). This was a randomized, placebo-controlled, crossover study involving 12 healthy subjects. Each subject ingested 750 mg of CBD solution, or alternatively, a placebo solution twice daily for a 3-day run-in period followed by an additional CBD dose (or placebo) and a single 10 mg dose of MPH and completed serial blood sampling for pharmacokinetic analysis. MPH and CBD concentrations were measured by liquid chromatography with tandem mass spectrometry.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 14

Inclusion Criteria

Signed Informed Consent
Age: 21-45 years
Gender: males and females (50:50)
Race or ethnicity: no restrictions
Body Mass Index (BMI) between 18.5 to 28 kg/m2 (inclusive)
Satisfactory completion of the screening medical history, physical exam, and laboratory evaluations.
Females of child-bearing potential must have a negative urine pregnancy test prior to enrollment and avoid pregnancy during study participation.
With the exception of oral contraceptives, subjects must not be taking prescription or OTC medication for the duration of study participation
Subjects must have no ongoing use of any botanical/nutritional supplement, vitamin, or energy drink for the duration of study participation

Exclusion Criteria

The presence of a known allergy, hypersensitivity, or adverse reaction to CBD or cannabis, or sesame seed oil
The presence of a known allergy, hypersensitivity, or adverse reaction to methylphenidate or dexmethylphenidate (Focalin®)
A history (within the past year) or presence of clinically significant cardiovascular, cerebrovascular, renal, hepatic, gastrointestinal, pulmonary, immunological, hematological, endocrine, or neurologic disease will render subjects ineligible for the study.
The presence of any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion including;
1. Gastric bezoar
2. Swallowing disorders
3. Strictures
4. Fistulas
5. GI obstruction
6. Severe dsyphasgia
7. Crohn's disease
8. Diverticulitis
9. A positive urine pregnancy test.
10. A positive Urine Drug Screen
11. Any concomitant prescription medication, OTC medication, herbal or other dietary supplement or vitamins during the study period.

All subjects must be medication-free from 7 Days before initiation of the first active study day, through the duration of the study. This exclusion the use of vitamins, herbal preparations and OTC supplements.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo, then CBD	dl-Methylphenidate plus Cannabidiol	Subjects received a three day run in of 7.5 ml of Epidiolex® placebo solution (no CBD) orally twice daily. On day four, all subjects returned to the clinical research center to receive one oral dose of 7.5 mL of Epidiolex® placebo solution (no CBD) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast). After a minimum washout period of five days, subjects received a three day run in of CBD 750 mg orally twice daily (administered as as 7.5 mL of Epidiolex® solution \[100 mg/ml\]). On day four, all subjects returned to the clinical research center to receive one oral dose of CBD 750 mg (administered as as 7.5 mL of Epidiolex® solution \[100 mg/ml\]) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast).
Placebo, then CBD	dl-Methylphenidate plus Cannabidiol Placebo solution	Subjects received a three day run in of 7.5 ml of Epidiolex® placebo solution (no CBD) orally twice daily. On day four, all subjects returned to the clinical research center to receive one oral dose of 7.5 mL of Epidiolex® placebo solution (no CBD) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast). After a minimum washout period of five days, subjects received a three day run in of CBD 750 mg orally twice daily (administered as as 7.5 mL of Epidiolex® solution \[100 mg/ml\]). On day four, all subjects returned to the clinical research center to receive one oral dose of CBD 750 mg (administered as as 7.5 mL of Epidiolex® solution \[100 mg/ml\]) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast).
CBD, then placebo	dl-Methylphenidate plus Cannabidiol	Subjects received a three day run in of CBD 750 mg orally twice daily (administered as as 7.5 mL of Epidiolex® solution \[100 mg/ml\]). On day four, all subjects returned to the clinical research center to receive one oral dose of CBD 750 mg (administered as as 7.5 mL of Epidiolex® solution \[100 mg/ml\]) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast). After a minimum washout period of five days, subjects received a three day run in of 7.5 ml of Epidiolex® placebo solution (no CBD) orally twice daily. On day four, all subjects returned to the clinical research center to receive one oral dose of 7.5 mL of Epidiolex® placebo solution (no CBD) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast).
CBD, then placebo	dl-Methylphenidate plus Cannabidiol Placebo solution	Subjects received a three day run in of CBD 750 mg orally twice daily (administered as as 7.5 mL of Epidiolex® solution \[100 mg/ml\]). On day four, all subjects returned to the clinical research center to receive one oral dose of CBD 750 mg (administered as as 7.5 mL of Epidiolex® solution \[100 mg/ml\]) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast). After a minimum washout period of five days, subjects received a three day run in of 7.5 ml of Epidiolex® placebo solution (no CBD) orally twice daily. On day four, all subjects returned to the clinical research center to receive one oral dose of 7.5 mL of Epidiolex® placebo solution (no CBD) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast).

Primary Outcome Measures

Name	Time	Method
Differences in the Geometric Mean Ratio (GMR) of the Peak Concentration (Cmax) Will be Compared Between the Two Exposure Conditions; i.e. Methylphenidate + CBD vs Methylphenidate + Placebo.	8 hours	Plasma methylphenidate (MPH) concentrations for both arms were determined by using a liquid-liquid extraction method and LC-MS/MS analysis. Peak concentration (Cmax) was reported as observed for each subject. The geometric mean ratios (GMR) of the Cmax for MPH were compared between the two exposure conditions, i.e., MPH with CBD versus MPH with placebo. In brief, if the 90% confidence interval (CI) of GMR for Cmax between the CBD group and placebo group extend beyond the FDA's established bioequivalent limits of 0.8-1.25, the result was interpreted to represent a DDI. In our case, a GMR greater than 1.25 would be indicative of a DDI, since CBD would impair CES1's ability to efficiently metabolize MPH, thus a higher ratio of Cmax's of MPH in our CBD group relative to our placebo group.
Differences in the Geometric Mean Ratio (GMR) of the Area Under the Time Curve 0-infinity (AUCinf) for Methylphenidate Will be Compared Between the Two Exposure Conditions; i.e. Methylphenidate + CBD vs Methylphenidate + Placebo.	0-8 hours (determined), 8 hours-infinity (extrapolated)	All methylphenidate plasma concentrations were quantified using liquid-liquid extraction method and LC-MS/MS analysis. The terminal elimination rate constant (λz) was estimated by linear least-squares regression of the terminal portion of the plasma concentration (on natural logarithmic scale)-time curve. The area under the plasma concentration-time curve of methylphenidate AUC 0-8h were calculated according to the linear trapezoidal rule. AUC8-inf was extrapolated by using the last observed concentration of MPH (Clast) and dividing it by λz. AUC0-8 was added to AUC8-inf to get AUCinf. The GMR of the AUCinf for MPH were compared between the two exposure conditions, i.e., MPH with CBD versus MPH with placebo. In brief, if the 90% confidence interval (CI) of GMR for Cmax between the CBD group and placebo group was beyond the FDA's established bioequivalent limits of 0.8-1.25, the result was interpreted to represent a DDI. A GMR greater than 1.25 would be indicative of a DDI.

Secondary Outcome Measures