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| ID | Type | Description | Link |
|---|---|---|---|
| OCR39758 | Other Identifier | UF OnCore |
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| Name | Class |
|---|---|
| Consortium for Medical Marijuana Clinical Outcomes Research | OTHER |
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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| CBD, then placebo | Experimental | 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). |
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| Placebo, then CBD | Experimental | 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). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| dl-Methylphenidate plus Cannabidiol | Drug | Subjects will be administered one 10 mg tablet of dl-methylphenidate (Ritalin®) plus 7.5 mL Epidiolex® solution |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. | 8 hours |
| 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. | 0-8 hours (determined), 8 hours-infinity (extrapolated) |
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| Measure | Description | Time Frame |
|---|---|---|
| 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). | 8 hours |
Inclusion Criteria:
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;
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.
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| Name | Affiliation | Role |
|---|---|---|
| John Markowitz, Pharm.D | University of Florida | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Florida | Gainesville | Florida | 32610 | United States |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | First Methylphenidate and CBD, Then Methylphenidate and Placebo | 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 orally (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). |
| FG001 | First Methylphenidate and Placebo, Then Methylphenidate and CBD | 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 orally (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). |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (4 Days) |
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| Washout (Minimum 5 Days) |
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| Second Intervention (4 Days) |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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). |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Geometric Mean | 90% Confidence Interval | Ratio | 8 hours |
Subjects participation lasted 45 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Methylphenidate and CBD Arms Only | 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 orally (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). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| John S. Markowitz, Pharm.D. | University of Florida | (352) 273-6262 | jmarkowitz@cop.ufl.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 25, 2022 | Feb 9, 2023 | Prot_SAP_001.pdf |
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| ID | Term |
|---|---|
| D002185 | Cannabidiol |
| D008774 | Methylphenidate |
| ID | Term |
|---|---|
| D002186 | Cannabinoids |
| D013729 | Terpenes |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
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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.
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| dl-Methylphenidate plus Cannabidiol Placebo solution | Drug | Subjects will be administered one 10 mg tablet of dl-methylphenidate (Ritalin®) plus 7.5 mL of Epidiolex® placebo solution |
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| 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. | 8 hours |
| 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. | 8 hours |
| 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. | 0-8 hours (determined), 8 hours-infinity (extrapolated) |
| 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. | 8 hours |
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| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| 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. | 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. | Posted | Geometric Mean | 90% Confidence Interval | Ratio | 0-8 hours (determined), 8 hours-infinity (extrapolated) |
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| 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). | 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. | Posted | Mean | Full Range | ng/mL | 8 hours |
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| 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. | 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. | Posted | Median | Full Range | hours (h) | 8 hours |
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| 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. | 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). | Posted | Mean | Full Range | ng/mL*h | 8 hours |
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| 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. | 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). | Posted | Mean | Full Range | ng/mL*h | 0-8 hours (determined), 8 hours-infinity (extrapolated) |
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| 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. | 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). | Posted | Mean | Full Range | hours (h) | 8 hours |
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| 0 |
| 14 |
| 0 |
| 14 |
| 1 |
| 14 |
| EG001 | Methylphenidate and Placebo Arms Only | 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). | 0 | 12 | 0 | 12 | 0 | 12 |
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| D010648 |
| Phenylacetates |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D010880 | Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |