Absorption; Chemicals
Conditions
Brief summary
Cannabidiol (CBD) has been approved as a treatment for rare childhood epilepsies and could be an effective treatment for psychotic disorders, anxiety disorders and addictions. It is available as an oral liquid and as standard oral capsules. The bioavailability of oral cannabidiol is poor (only around 5-10% is absorbed), particularly in the fasted state. With food, its absorption is much higher. In one study, a high-fat breakfast increased the maximum plasma concentration by 4-5 times. As a result of this food effect, when prescribing standard oral formulations of CBD, clinicians should provide advice on dosing the drug according to mealtimes, otherwise, there may be an increased risk of side effects or limited effectiveness. One way to reduce the food effect and improve bioavailability is to use lipid excipients. In the present study, the investigators will evaluate CBD at the dose that is effective in patients with chronic psychosis (1000mg). The novel formulation will use lipids that are all EU pharmacopoeia approved and have been used in medicinal products before. The study aims to assess whether a novel lipid formulation can increase the bioavailability of oral CBD in the fasting state.
Interventions
DRUGStandard formulation
Cannabidiol 1000mg standard formulation, single dose, oral
DRUGNovel formulation
Cannabidiol 1000mg with lipid matrix, single dose, oral
Sponsors
King's College London
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
i. Healthy volunteers. Defined as healthy on the basis of a clinical history, physical examination, ECG, vital signs, and laboratory tests of blood and urine. ii. Age 18-45 iii. Agreeing to fast 15 hours; 10pm-1pm on dosing days iv. Capable of giving informed consent v. Written informed consent from participant
Exclusion criteria
i. Clinically relevant medical history, physical findings, ECG, or laboratory values at the pre-trial screening assessment that could interfere with the objectives of the trial or the safety of the participant. ii. Presence of acute or chronic illness or history of chronic illness sufficient to invalidate the volunteer's participation in the trial or make it unnecessarily hazardous. iii. Impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes mellitus, coronary heart disease, or history of any neurological or mental illness. iv. Surgery or medical condition that might affect absorption of medicines. v. Blood pressure and heart rate in supine position at the screening examination outside the ranges: blood pressure 90-140 mm Hg systolic, 40-90 mm Hg diastolic; heart rate 40-100 beats/min. Repeat measurements are permitted if values are borderline (i.e. values that are within 5 mm Hg for blood pressure or 5 beats/min for heart rate) or if requested by the investigator. Subjects can be included if the repeat value is within range or still borderline but deemed not clinically significant by the investigator. vi. Loss of more than 400 mL blood during the 3 months before the trial, e.g. as a blood donor. vii. Any prescribed medication (apart from contraceptives) viii. Use of any CBD products within six months of IMP administration ix. Use of any over-the-counter medications or health supplements within the past 2 weeks x. BMI \<18 or \>30.0kg/m2 xi. History of alcohol or substance misuse disorder xii. Intake of more than 14 units of alcohol weekly. xiii. Smokes more than 10 cigarettes per day xiv. Use of any illicit substances within the last six months of IMP administration xv. Pregnant or breastfeeding xvi. Women of childbearing potential (as defined in CTFG guidelines, see 5.7 Concomitant Medication) not willing to use a highly effective form of contraception (as defined in CTFG guidelines, see section 5.7 Concomitant Medication) during participation in the study or male patients not willing to ensure use of a condom during participation in the study. xvii. eGFR≤ 70 mls/min xviii. Any liver function or renal function test abnormality. A repeat is allowed on one occasion for determination of eligibility. xix. Urine drug screen positive for any substances xx. Positive alcohol breath test xxi. Participant in any other clinical trial or experimental drug study in the past 3 months xxii. Known hypersensitivity to CBD and/or SEEK formulation excipients xxiii. Participant is not able to swallow capsules
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Drug Exposure. (Area Under the Curve to Infinity [AUC(Inf)] | 0 - 48 hours | Difference in AUC(inf) for a single dose of oral CBD between the novel and standard formulations in the fasting state. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax | 0 - 48 hours | Maximum plasma concentration |
| Tmax | 0 - 48 hours | Time after administration of drug when maximum plasma concentration is reached |
| Plasma Half-life (t½) | 0 - 48 hours | Half-life |
| 48 Hour Drug Exposure (AUC0-48) | 0 - 48 hours | Area under the concentration-time curve from time zero to 48hours |
| Gastrointestinal Symptom Rating Scale (GSRS) - Total Score | The scale will be used pre-dose and at 24 and 48 hours post dose. | The GSRS was used to assess gastrointestinal symptoms over the past 24 hours only. It is a 15-item rating scale, where each item is assessed with a 7-point Likert scale, scored from 1 to 7, and with higher scores indicating more severe symptoms. The total score is the mean score across items (minimum score=1; maximum sore=7). |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Novel Lipid Formulation Then Standard Formulation Period 1: Cannabidiol 1000mg with lipid matrix, single dose, oral
Period 2: Cannabidiol standard formulation: Cannabidiol 1000mg standard formulation, single dose, oral | 7 |
| Standard Formulation Then Novel Lipid Formulation Period 1: Cannabidiol standard formulation: Cannabidiol 1000mg standard formulation, single dose, oral
Period 2: Cannabidiol novel formulation: Cannabidiol 1000mg with lipid matrix, single dose, oral | 7 |
| Total | 14 |
Baseline characteristics
| Characteristic | Standard Formulation Then Novel Lipid Formulation | Total | Novel Lipid Formulation Then Standard Formulation |
|---|---|---|---|
| Age, Continuous | 26.7 years STANDARD_DEVIATION 5.1 | 26.7 years STANDARD_DEVIATION 4.5 | 26.7 years STANDARD_DEVIATION 4.4 |
| Race/Ethnicity, Customized Asian | 1 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 9 Participants | 4 Participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 11 / 14 | 8 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 |
Outcome results
Primary
Total Drug Exposure. (Area Under the Curve to Infinity [AUC(Inf)]
Difference in AUC(inf) for a single dose of oral CBD between the novel and standard formulations in the fasting state.
Time frame: 0 - 48 hours
Population: AUCinf could not be calculated for three participants in the standard CBD arm as plasma levels were not falling at the final time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Novel Lipid Formulation Cannabidiol | Total Drug Exposure. (Area Under the Curve to Infinity [AUC(Inf)] | 674.9 ng*h/ml | Geometric Coefficient of Variation 103.05 |
| Standard Formulation Cannabidiol | Total Drug Exposure. (Area Under the Curve to Infinity [AUC(Inf)] | 134.76 ng*h/ml | Geometric Coefficient of Variation 88.7 |
Secondary
48 Hour Drug Exposure (AUC0-48)
Area under the concentration-time curve from time zero to 48hours
Time frame: 0 - 48 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Novel Lipid Formulation Cannabidiol | 48 Hour Drug Exposure (AUC0-48) | 611.42 ng*h/ml | Geometric Coefficient of Variation 104.6 |
| Standard Formulation Cannabidiol | 48 Hour Drug Exposure (AUC0-48) | 66.79 ng*h/ml | Geometric Coefficient of Variation 50.65 |
Secondary
Cmax
Maximum plasma concentration
Time frame: 0 - 48 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Novel Lipid Formulation Cannabidiol | Cmax | 73.00 ng/ml | Geometric Coefficient of Variation 149.82 |
| Standard Formulation Cannabidiol | Cmax | 3.11 ng/ml | Geometric Coefficient of Variation 103.55 |
Secondary
Gastrointestinal Symptom Rating Scale (GSRS) - Total Score
The GSRS was used to assess gastrointestinal symptoms over the past 24 hours only. It is a 15-item rating scale, where each item is assessed with a 7-point Likert scale, scored from 1 to 7, and with higher scores indicating more severe symptoms. The total score is the mean score across items (minimum score=1; maximum sore=7).
Time frame: The scale will be used pre-dose and at 24 and 48 hours post dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Novel Lipid Formulation Cannabidiol | Gastrointestinal Symptom Rating Scale (GSRS) - Total Score | Baseline/pre-dose | 1.09 Mean score | Standard Deviation 0.17 |
| Novel Lipid Formulation Cannabidiol | Gastrointestinal Symptom Rating Scale (GSRS) - Total Score | 24 hours post dose | 1.25 Mean score | Standard Deviation 0.36 |
| Novel Lipid Formulation Cannabidiol | Gastrointestinal Symptom Rating Scale (GSRS) - Total Score | 48 hours post dose | 1.09 Mean score | Standard Deviation 0.18 |
| Standard Formulation Cannabidiol | Gastrointestinal Symptom Rating Scale (GSRS) - Total Score | Baseline/pre-dose | 1.06 Mean score | Standard Deviation 0.09 |
| Standard Formulation Cannabidiol | Gastrointestinal Symptom Rating Scale (GSRS) - Total Score | 24 hours post dose | 1.06 Mean score | Standard Deviation 0.11 |
| Standard Formulation Cannabidiol | Gastrointestinal Symptom Rating Scale (GSRS) - Total Score | 48 hours post dose | 1.02 Mean score | Standard Deviation 0.04 |
Secondary
Plasma Half-life (t½)
Half-life
Time frame: 0 - 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Novel Lipid Formulation Cannabidiol | Plasma Half-life (t½) | 13.71 hours | Standard Deviation 5.89 |
| Standard Formulation Cannabidiol | Plasma Half-life (t½) | 51.83 hours | Standard Deviation 57.61 |
Secondary
Tmax
Time after administration of drug when maximum plasma concentration is reached
Time frame: 0 - 48 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Novel Lipid Formulation Cannabidiol | Tmax | 4 hours |
| Standard Formulation Cannabidiol | Tmax | 6 hours |