Use of cannabinoids in the treatment of epilepsy

Abstract

The present invention relates to the use of cannabidiol (CBD) in the treatment of patients with childhood-onset epilepsy who are concurrently taking immunosuppressant drugs. In particular the immunosuppressant drug is a calcineurin inhibitor. More particularly the immunosuppressant drug is tacrolimus. Where the CBD is used in combination with an immunosuppressant drug, caution should be taken. For example, the dose of either the CBD and/or the immunosuppressant drug may be required to be reduced. Moreover, the patient may need to be monitored for side effects of said drug-drug interaction. Preferably the CBD used is in the form of a highly purified extract of cannabis such that the CBD is present at greater than 98% of the total extract (w/w) and the other components of the extract are characterised. In particular the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level of not more than 0.15% (w/w) and the propyl analogue of CBD, cannabidivarin, (CBDV) is present in amounts of up to 1%. Alternatively, the CBD may be a synthetically produced CBD.

Claims

1. A method of treating childhood-onset epilepsy in a patient who is concurrently taking tacrolimus, comprising: administering to the patient a drug substance comprising at least 98% (w/w) cannabidiol (CBD) and less than 0.15% (w/w) THC; detecting toxic blood levels of tacrolimus or one or more associated markers; and reducing the dose of tacrolimus to no more than 5 mg per day.

2. The method according to claim 1, wherein the dose of CBD is lowered.

3. The method according to claim 1, wherein the drug substance is in the form of a highly purified extract of cannabis which comprises at least 98% (w/w) CBD.

4. The method according to claim 1, wherein the CBD is present as a synthetic compound.

5. The method according to claim 3, wherein the extract further comprises up to 1% (w/w) CBDV.

6. The method according to claim 1, wherein the dose of CBD is below 50 mg/kg/day.

7. The method according to claim 1, wherein the dose of CBD is greater than 20 mg/kg/day.

8. The method according to claim 1, wherein the childhood-onset epilepsy is: Lennox-Gastaut Syndrome; Myoclonic Absence Epilepsy; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; Jeavons Syndrome; CDKL5; Dup15q; Neuronal ceroid lipofuscinoses (NCL) or brain abnormalities.

9. The method of claim 1, wherein the associated markers comprise serum creatine.

10. The method of claim 9, wherein the serum creatine become toxic when the blood levels are 2.4 mg/dL or more.

11. The method of claim 1, wherein the dose of tacrolimus is reduced by up to 10-fold.

12. The method of claim 1, wherein the dose of tacrolimus is reduced to 0.5 mg twice per day.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which

(2) FIG. 1 shows the Daily doses of Tacrolimus (Tac) and Cannabidiol (CBD) during study period; and

(3) FIG. 2 shows the Tacrolimus dose normalised trough concentration.

DETAILED DESCRIPTION

(4) Preparation of Highly Purified CBD Extract

(5) The following describes the production of the highly-purified (>98% w/w) cannabidiol extract which has a known and constant composition was used in the Examples below.

(6) In summary the drug substance used is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD. The crystallisation process specifically removes other cannabinoids and plant components to yield greater than 98% CBD. Although the CBD is highly purified because it is produced from a cannabis plant rather than synthetically there is a small number of other cannabinoids which are co-produced and co-extracted with the CBD. Details of these cannabinoids and the quantities in which they are present in the medication are as described in Table 5 below.

(7) TABLE-US-00005 TABLE 5 Composition of highly purified CBD extract Cannabinoid Concentration CBD >98% w/w CBDA NMT 0.15% w/w CBDV NMT 1.0% w/w .sup.9 THC NMT 0.15% w/w CBD-04 NMT 0.5% w/w >greater than NMTnot more than

Example 1: Drug-Drug Interaction Between Cannabidiol (CBD) and Immunosuppressants

(8) The patient was a 33 year old female with refractory epilepsy receiving the immunosuppressant drug tacrolimus for interstitial nephritis.

(9) The patient had been stable on tacrolimus at a dose of 5 mg twice per day for a year prior to entry into a clinical trial on the use of CBD to treat childhood-onset epilepsy. At the time of entry into the study her blood level of tacrolimus was between 3.9 and 8.4 ng/mL. She also had a baseline Serum Creatine level of 1.16 mg/dL.

(10) The patient was initially randomized to the sesame oil placebo arm of the trial, during this phase there was no change in the levels of tacrolimus or serum creatine.

(11) However, when the patient entered into the open label phase of the study and began receiving CBD she showed signs of tacrolimus toxicity with a serum creatine level of 2.4 mg/dL.

(12) The dose of tacrolimus was reduced repeatedly while receiving CBD as described in FIG. 1. A dose of 0.5 mg twice per day (a 10-fold reduction) was finally reached. At this dose the tacrolimus concentrations were normalised as shown in FIG. 2.

(13) Such a finding delineates an important concern for the transplant community with the increasing legalization of marijuana. This drug-drug interaction may have implications in solid organ transplant recipients which are not correctly monitored over the course of their treatment.

CONCLUSIONS

(14) Patients that are taking immunosuppressant drugs such as tacrolimus should be carefully monitored over the course of their treatment with CBD to ensure toxicity does not occur.