Clinical trial NCT04603391: Cannabidiol and CES1 Interactions in Healthy Subjects
Official title: An Assessment of the Drug Interaction Potential Between Oral Cannabidiol (Epidiolex®) and the CES1 Substrate Methylphenidate in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Drug Interaction
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: Consortium for Medical Marijuana Clinical Outcomes Research
First posted: 2020-10-26
Enrollment: 14
Sex: ALL
Minimum age (years): 21
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: An open-label, randomized crossover design is proposed wherein healthy volunteer subjects (n=12) would receive a single dose of immediate-release dl-methylphenidate (Ritalin®) concomitantly with orally administered CBD (Epidiolex®) solution or an equal volume of Epidiolex® placebo solution (i.e vehicle with no CBD) which have been dosed to plasma steady-state conditions.
Primary purpose: OTHER

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: 8 hours
measure: 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.
timeFrame: 0-8 hours (determined), 8 hours-infinity (extrapolated)
Secondary outcomes:
Other outcomes:
measure: Peak Methylphenidate Plasma Concentration (Cmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms.
timeFrame: 8 hours
measure: Time to Peak Methylphenidate Plasma Concentration (Tmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms.
timeFrame: 8 hours
measure: Area Under the Time Curve 0-8hours (AUC0-8h) for Methylphenidate for the Two Exposure Conditions; Methylphenidate and CBD and Methylphenidate and Placebo.
timeFrame: 8 hours
measure: Area Under the Time Curve 0-infinity (AUCinf) for Methylphenidate for the Two Exposure Conditions for Methylphenidate and CBD and Methylphenidate and Placebo.
timeFrame: 0-8 hours (determined), 8 hours-infinity (extrapolated)
measure: Half Life Determination (t1/2) for Methylphenidate for the Two Exposure Conditions for Methylphenidate and CBD and Methylphenidate and Placebo.
timeFrame: 8 hours
Locations:
city: Gainesville
country: United States
facility: University of Florida
state: Florida
Study officials:
affiliation: University of Florida
name: John Markowitz, Pharm.D
role: PRINCIPAL_INVESTIGATOR
References: