Study to Evaluate the Effect of Rifampicin, Ketoconazole, and Omeprazole on the Pharmacokinetics of Sativex

Study Overview
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Brief Summary
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Study to assess the effect of rifampicin, ketoconazole and omeprazole on the pharmacokinetics of a single dose of Sativex and to evaluate the safety of Sativex when given in combination with these other drugs.

Detailed Description
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An open-label, randomised, crossover, drug interaction study. Subjects were divided into three groups and within each group, subjects were randomised to one of two treatment sequences. Subjects received 4 sprays of Sativex alongside either doses of rifampicin, ketoconazole or omeprazole.

Official Title
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A Phase I, Open-label, Randomised, Crossover Study in 3 Parallel Groups to Evaluate the Effect of Rifampicin, Ketoconazole, and Omeprazole on the Pharmacokinetics of Sativex in Healthy Volunteers

Conditions
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Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a Known Inducer of CYP3A4, Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a Potent Inhibitor of CYP3A4, Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a CYP2C19 Inhibitor

Intervention / Treatment
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* Drug: Sativex and rifampicin
* Drug: Sativex and rifampicin
* Drug: Sativex and ketoconazole
* Drug: Sativex and ketoconazole
* Drug: Sativex and omeprazole
* Drug: Sativex and omeprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male subjects between 18 and 45 years of age (inclusive). Subjects body mass index was between 18-30 kg/m2 (inclusive) as calculated by: Weight (kg)/height (m2). No clinically significant abnormal findings on the physical examination, ECG, medical history, or clinical laboratory results during screening. Subjects were to, in the opinion of the investigator, have no clinically significant abnormal findings of renal and hepatic function as determined by serum creatinine, total bilirubin, and transaminase levels. Subjects were to be non-users of tobacco products (minimum of 6 months prior to the start of the study). Subjects were to have a negative screen for HIV I and II, HBsAg. and antibody to hepatitis C. Subjects were to have a negative urine screen for alcohol, drugs of abuse (screening only), and cotinine. Subjects were to use an appropriate barrier method of contraception (condom and spermicide) in addition to having their female partner use another form of barrier contraception (e.g. female condom or occlusive cap [diaphragm or cervical vault/caps] with spermicide) during the study and for 3 months following administration of the study drug. Subjects were to be able to comply with the protocol and the restrictions and the assessments therein. Subjects were to give voluntary written informed consent to participate in the trial. Exclusion Criteria: Subjects were not to have a history or presence of significant cardiovascular, pulmonary, hepatic, renal, haematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease. Subjects were not to have any history or presence of family history of schizophrenia, other psychotic illness, severe personality disorder, depression, or other significant psychiatric disorder. Subjects were not to have a postural drop of 20 mmHG or more in systolic blood pressure at screening. Subjects were not to have participated in a previous clinical trial within 90 days prior to study initiation. Subjects were not to have donated plasma within 90 days prior to study initiation. Subjects were not to have donated blood within 90 days prior to study initiation. Subjects were not to have had an abnormal diet or substantial changes in eating habits within 30 days prior to study initiation. Subjects were not to have had treatment with any known enzyme-altering agents (barbiturates, phenothiazines, cimetidine etc.) within 30 days prior to or during the study. Subjects were to have no history of known hypersensitivity or idiosyncratic reaction to the study drugs or related compounds. Subjects were not to use any prescription medication within 14 days prior to or during the study. Subjects were not to use any over-the-counter medication within 7 days prior to or during the study. Subjects were not to have a history of alcohol or drug abuse within 2 years prior to the study (subjects with a history of previous use of cannabis were not excluded unless they had used cannabis or cannabinoid based medicine within 30 days prior to study drug administration or were unwilling to abstain for the duration of the study).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence 1A<br>Sativex and rifampicin | Drug: Sativex and rifampicin<br>* Single dose of 4 sprays Sativex on Day 1, Rifampicin 2 x 300 mg capsules on Days 2-10, Sativex dose of 4 sprays and rifampicin 2 x 300 mg capsules on Day 11.<br>|
| Experimental: Sequence 1B<br>Sativex and rifampicin | Drug: Sativex and rifampicin<br>* Rifampicin 2 x 300 mg capsules on Days 1-9, Sativex x 4 sprays and rifampicin 2 x 300 mg capsules on Day 10, Single dose of Sativex 4 sprays on Day 18.<br>|
| Experimental: Sequence 2C<br>Sativex and ketoconazole | Drug: Sativex and ketoconazole<br>* Single dose of 4 sprays Sativex on Day 1, ketoconazole 2 x 200 mg tablets on Days 2-5, Sativex x 4 sprays and ketoconazole 2 x 200mg on Day 6.<br>|
| Experimental: Sequence 2D<br>Sativex and ketoconazole | Drug: Sativex and ketoconazole<br>* Ketoconazole 2 x 200 mg tablets on Days 1-4, Sativex x 4 sprays and ketoconazole 2 x 200 mg tablets on Day 5, Single dose of 4 sprays Sativex on Day 9.<br>|
| Experimental: Sequence 3E<br>Sativex and omeprazole | Drug: Sativex and omeprazole<br>* Single dose of 4 sprays of Sativex on Day 1 Omeprazole 2 x 20 mg on Days 2-6. Sativex x 4 sprays and omeprazole 2 x 20 mg on Day 9.<br>|
| Experimental: Sequence 3F<br>Sativex and omeprazole | Drug: Sativex and omeprazole<br>* Omeprazole 2 x 20 mg on Days 1-5, Sativex x 4 sprays and omeprazole 2 x 20 mg on Day 6, Single dose of 4 sprays Sativex on Day 9.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic analysis - Cmax of Sativex® alone and of Sativex® with concomitant administration of rifampicin, ketoconazole, and omeprazole |  | Up to Day 8 | 
| Pharmacokinetic analysis - AUC(0-t) of Sativex® alone and of Sativex® with concomitant administration of rifampicin, ketoconazole, and omeprazole |  | Up to day 8 | 
| Pharmacokinetic analysis - AUC(0-inf) of Sativex® alone and of Sativex® with concomitant administration of rifampicin, ketoconazole, and omeprazole |  | Up to Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events |  | Up to follow up, Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sativex, Cytochrome P450, Pharmacokinetics, Cannabinoids, ketoconazole, omeprazole, rifampicin