Drug Interaction
Conditions
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.
Interventions
DRUGdl-Methylphenidate plus Cannabidiol
Subjects will be administered one 10 mg tablet of dl-methylphenidate (Ritalin®) plus 7.5 mL Epidiolex® solution
DRUGdl-Methylphenidate plus Cannabidiol Placebo solution
Subjects will be administered one 10 mg tablet of dl-methylphenidate (Ritalin®) plus 7.5 mL of Epidiolex® placebo solution
Sponsors
Consortium for Medical Marijuana Clinical Outcomes Research
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
SINGLE (Subject)
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.
Eligibility
Sex/Gender
ALL
Age
21 Years to 45 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Time Curve 0-8hours (AUC0-8h) for Methylphenidate for the Two Exposure Conditions; Methylphenidate and CBD and Methylphenidate and Placebo. | 8 hours | All methylphenidate plasma concentrations were quantified using liquid-liquid extraction method and LC-MS/MS analysis. The area under the plasma concentration-time curve of methylphenidate AUC 0-8h was calculated according to the linear trapezoidal rule. |
| Peak Methylphenidate Plasma Concentration (Cmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms. | 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 (highest observed plasma concentration of methylphenidate). |
| Half Life Determination (t1/2) for Methylphenidate for the Two Exposure Conditions for Methylphenidate and CBD and Methylphenidate and Placebo. | 8 hours | 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 elimination half-live (t1/2) was then calculated using the formula t1/2 = 0.693/λz. |
| Area Under the Time Curve 0-infinity (AUCinf) for Methylphenidate for the Two Exposure Conditions for Methylphenidate and CBD and Methylphenidate and 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. |
| Time to Peak Methylphenidate Plasma Concentration (Tmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms. | 8 hours | Plasma methylphenidate (MPH) concentrations for both arms were determined by using a liquid-liquid extraction method and LC-MS/MS analysis. The time to peak plasma methylphenidate concentrations (Tmax) was reported as observed for each subject. |
Countries
United States
Participant flow
Pre-assignment details
After enrollment, subjects were assigned a screening visit date at the Clinical Research Center to obtain a medical history, physical, and routine lab tests including a complete blood count, comprehensive metabolic panel, urinalysis, and urine drug screen.
Participants by arm
| Arm | Count |
|---|---|
| All Study Subjects for Both Sequences Sequence 1: Subjects received a three day run in of 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 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 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 and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast).
Sequence 2: Subjects received a three day run in of 7.5 ml of Epidiolex® placebo solution 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 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® solution \[100 mg/ml\]). On day four, all subjects returned to the clinical research center to receive one oral dose 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). | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (4 Days) | Adverse Event | 1 | 0 |
| First Intervention (4 Days) | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | All Study Subjects for Both Sequences |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Age, Continuous | 26.67 years STANDARD_DEVIATION 6.54 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 14 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 12 |
| other Total, other adverse events | 1 / 14 | 0 / 12 |
| serious Total, serious adverse events | 0 / 14 | 0 / 12 |
Outcome results
Primary
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.
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.
Time frame: 0-8 hours (determined), 8 hours-infinity (extrapolated)
Population: Each subject served as their own control, so since all 12 subjects that completed the study went through both arms, we were able to analyze the both arms for each subject. Hence, 12 subjects gave us 24 arms (2 arms/subject). The AUCinf for each subject in the methylphenidate and CBD arm was directly compared to their methylphenidate and placebo arm, allowing us to determine the ratio of change in the presence of CBD.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| All Participants | 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. | 1.09 Ratio |
Primary
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.
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.
Time frame: 8 hours
Population: Each subject served as their own control, so since all 12 subjects that completed the study went through both arms, we were able to analyze the both arms for each subject. Hence, 12 subjects gave us 24 arms (2 arms/subject). The Cmax for each subject in the methylphenidate and CBD arm was directly compared to their methylphenidate and placebo arm, allowing us to determine the ratio of change in the presence of CBD.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| All Participants | 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. | 1.08 Ratio |
Other Pre-specified
Area Under the Time Curve 0-8hours (AUC0-8h) for Methylphenidate for the Two Exposure Conditions; Methylphenidate and CBD and Methylphenidate and Placebo.
All methylphenidate plasma concentrations were quantified using liquid-liquid extraction method and LC-MS/MS analysis. The area under the plasma concentration-time curve of methylphenidate AUC 0-8h was calculated according to the linear trapezoidal rule.
Time frame: 8 hours
Population: Each subject served as their own control, so since all 12 subjects that completed the study went through both arms, we were able to analyze the both arms for each subject. Hence, 12 subjects gave us 24 arms (2 arms/subject).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| All Participants | Area Under the Time Curve 0-8hours (AUC0-8h) for Methylphenidate for the Two Exposure Conditions; Methylphenidate and CBD and Methylphenidate and Placebo. | 55.7 ng/mL*h |
| Methylphenidate and Placebo Arm Only | Area Under the Time Curve 0-8hours (AUC0-8h) for Methylphenidate for the Two Exposure Conditions; Methylphenidate and CBD and Methylphenidate and Placebo. | 49.6 ng/mL*h |
Other Pre-specified
Area Under the Time Curve 0-infinity (AUCinf) for Methylphenidate for the Two Exposure Conditions for Methylphenidate and CBD and Methylphenidate and Placebo.
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.
Time frame: 0-8 hours (determined), 8 hours-infinity (extrapolated)
Population: Each subject served as their own control, so since all 12 subjects that completed the study went through both arms, we were able to analyze the both arms for each subject. Hence, 12 subjects gave us 24 arms (2 arms/subject).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| All Participants | Area Under the Time Curve 0-infinity (AUCinf) for Methylphenidate for the Two Exposure Conditions for Methylphenidate and CBD and Methylphenidate and Placebo. | 70.7 ng/mL*h |
| Methylphenidate and Placebo Arm Only | Area Under the Time Curve 0-infinity (AUCinf) for Methylphenidate for the Two Exposure Conditions for Methylphenidate and CBD and Methylphenidate and Placebo. | 63.6 ng/mL*h |
Other Pre-specified
Half Life Determination (t1/2) for Methylphenidate for the Two Exposure Conditions for Methylphenidate and CBD and Methylphenidate and Placebo.
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 elimination half-live (t1/2) was then calculated using the formula t1/2 = 0.693/λz.
Time frame: 8 hours
Population: Each subject served as their own control, so since all 12 subjects that completed the study went through both arms, we were able to analyze the both arms for each subject. Hence, 12 subjects gave us 24 arms (2 arms/subject).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| All Participants | Half Life Determination (t1/2) for Methylphenidate for the Two Exposure Conditions for Methylphenidate and CBD and Methylphenidate and Placebo. | 3.17 hours (h) |
| Methylphenidate and Placebo Arm Only | Half Life Determination (t1/2) for Methylphenidate for the Two Exposure Conditions for Methylphenidate and CBD and Methylphenidate and Placebo. | 3.12 hours (h) |
Other Pre-specified
Peak Methylphenidate Plasma Concentration (Cmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms.
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 (highest observed plasma concentration of methylphenidate).
Time frame: 8 hours
Population: Each subject served as their own control, so since all 12 subjects that completed the study went through both arms, we were able to analyze the both arms for each subject. Hence, 12 subjects gave us 24 arms (2 arms/subject). The Cmax for each subject in the methylphenidate and CBD arm and the methylphenidate and placebo arm was directly reported/analyzed below.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| All Participants | Peak Methylphenidate Plasma Concentration (Cmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms. | 13.5 ng/mL |
| Methylphenidate and Placebo Arm Only | Peak Methylphenidate Plasma Concentration (Cmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms. | 12.2 ng/mL |
Other Pre-specified
Time to Peak Methylphenidate Plasma Concentration (Tmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms.
Plasma methylphenidate (MPH) concentrations for both arms were determined by using a liquid-liquid extraction method and LC-MS/MS analysis. The time to peak plasma methylphenidate concentrations (Tmax) was reported as observed for each subject.
Time frame: 8 hours
Population: Each subject served as their own control, so since all 12 subjects that completed the study went through both arms, we were able to analyze the both arms for each subject. Hence, 12 subjects gave us 24 arms (2 arms/subject). The Tmax for each subject in the methylphenidate and CBD arm and the methylphenidate and placebo arm was directly reported/analyzed below.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Time to Peak Methylphenidate Plasma Concentration (Tmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms. | 1.25 hours (h) |
| Methylphenidate and Placebo Arm Only | Time to Peak Methylphenidate Plasma Concentration (Tmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms. | 1.75 hours (h) |