An Open Label, Single-dose, Parallel Group Study to Assess the Pharmacokinetics and Tolerability of a Single Oromucosal Dose of 4 Sprays of Sativex(Containing 10.8 mg Delta-9-tetrahydrocannabinol [THC] and 10 mg Cannabidiol [CBD]) in Patients With Impaired Hepatic Function and Healthy Subjects With Normal Hepatic Function.
Overview
- Phase
- Phase 1
- Intervention
- Sativex
- Conditions
- Hepatic Impairment
- Sponsor
- Jazz Pharmaceuticals
- Enrollment
- 32
- Locations
- 2
- Primary Endpoint
- Pharmacokinetic analysis - Unbound maximum plasma concentration (Cmax(u)) of Sativex® in healthy patients and in patients with hepatic impairment
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
A Phase I open-label study to evaluate the pharmacokinetics (what the body does to a drug), safety and tolerability of a single dose of Sativex (containing 10.8 mg tetrahydrocannabinol [THC] and 10 mg cannabidiol [CBD]) in healthy patients and those with hepatic (liver) function impairment.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subject is aged 18 years or above.
- •Subject is willing and able to give informed consent for participation in the study (see Section 14.2).
- •Male or female subjects.
- •All females must have negative pregnancy test results at screening and baseline.
- •Vital signs (after five minutes resting measured in the supine position) must be within the following ranges:
- •Body temperature between 35.0-37.5 °C
- •Systolic blood pressure, 90-150 mmHg
- •Diastolic blood pressure, 60-90 mmHg
- •Pulse rate, 40-99 beats per minute (bpm) Blood pressure and pulse will be taken again in a standing position. After two minutes standing, there shall be no more than a 20 mmHg drop in systolic or 10 mmHg drop in diastolic blood pressure, associated with clinical manifestation of postural hypotension.
- •Subjects must weigh at least 50 kg and have a BMI between 19 and 42 kg/m2 to participate in this study.
Exclusion Criteria
- •Donation or loss of 400 mL or more of blood within eight weeks prior to dosing.
- •Significant concomitant illness within the two weeks prior to dosing.
- •Resting heart rate \<40 bpm.
- •History of autonomic dysfunction.
- •History of clinically significant drug allergy; a known hypersensitivity to the study drug or drugs similar to the study drug.
- •Any surgical or medical condition (other than hepatic impairment) which might significantly alter the absorption, distribution, metabolism or excretion of drugs, or which may jeopardize the subject in case of participation in the study.
- •Any history of significant bleeding and haemorrhagic tendencies. However, subjects with a history of bleeding tendencies secondary to hepatic impairment will be excluded based on Principal Investigators' discretion.
- •History of immunocompromisation, including known history of human immunodeficiency virus seropositivity.
- •History of drug abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during the screening or baseline evaluations.
- •Unwilling to abstain from alcohol during this study.
Arms & Interventions
Group 1: mild hepatic impairment
Mild hepatic impairment: eight patients of Child-Pugh Grade A (Score 5-6). All patients received Sativex treatment.
Intervention: Sativex
Group 2: Moderate hepatic impairment
Moderate hepatic impairment: eight patients of Child-Pugh Grade B (Score 7-9). All patients received Sativex treatment.
Intervention: Sativex
Group 3: Pugh Grade B (Score 7-9).
Severe hepatic impairment: eight patients of Child-Pugh Grade C (Score 10-15). All patients received Sativex treatment.
Intervention: Sativex
Group 4: Control group
Control Group: eight healthy subjects matched with respect to age (±10 years), weight (±10% body mass index \[BMI\]) and sex to the severe or most severe evaluable patients. All patients received Sativex treatment.
Intervention: Sativex
Outcomes
Primary Outcomes
Pharmacokinetic analysis - Unbound maximum plasma concentration (Cmax(u)) of Sativex® in healthy patients and in patients with hepatic impairment
Time Frame: Pre-dose (0),0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 11, 24, 36 and 48 hours post dose.
All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. For pharmacokinetic (PK) assessments, blood will be drawn from each patient into a five mL lithium-heparinised tube at the following intervals (±five min): Pre-dose (0),0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 11, 24, 36 and 48 hours post dose. Collected blood samples will be used to confirm correct dosing, and to provide information about the plasma concentrations of unbound THC, CBD, 11-hydroxy-THC (11-OH-THC), 6-hydroxy-CBD (6-OH-CBD) and 7-hydroxy-CBD (7-OH-CBD).
Pharmacokinetic analysis - Unbound area under the concentration-time curve calculated to the last observable concentration at time t (AUC0-t(u)) of Sativex® in healthy patients and in patients with hepatic impairment
Time Frame: Pre-dose (0),0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 11, 24, 36 and 48 hours post dose.
All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. For pharmacokinetic (PK) assessments, blood will be drawn from each patient into a five mL lithium-heparinised tube at the following intervals (±five min): Pre-dose (0),0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 11, 24, 36 and 48 hours post dose. Collected blood samples will be used to confirm correct dosing, and to provide information about the plasma concentrations of unbound THC, CBD, 11-OH-THC, 6-OH-CBD and 7-OH-CBD.
Pharmacokinetic analysis - Unbound Area under the concentration-time curve from time zero to infinity (AUC0-inf(u)) of Sativex® in healthy patients and in patients with hepatic impairment
Time Frame: Pre-dose (0),0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 11, 24, 36 and 48 hours post dose.
All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. For pharmacokinetic (PK) assessments, blood will be drawn from each patient into a five mL lithium-heparinised tube at the following intervals (±five min): Pre-dose (0),0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 11, 24, 36 and 48 hours post dose. Collected blood samples will be used to confirm correct dosing, and to provide information about the plasma concentrations of unbound THC, CBD, 11-OH-THC, 6-OH-CBD and 7-OH-CBD.
Secondary Outcomes
- Pharmacokinetic analysis - Area under the concentration-time curve calculated to the last observable concentration at time t (AUC0-t) of Sativex® in healthy patients and in patients with hepatic impairment(Pre-dose (0),0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 11, 24, 36 and 48 hours post dose.)
- Pharmacokinetic analysis - Area under the concentration-time curve from time zero to infinity (AUC0-inf) of Sativex® in healthy patients and in patients with hepatic impairment(Pre-dose (0),0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 11, 24, 36 and 48 hours post dose.)
- Pharmacokinetic analysis - time to peak concentration (Tmax) of Sativex® in healthy patients and in patients with hepatic impairment(Pre-dose (0),0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 11, 24, 36 and 48 hours post dose.)
- Pharmacokinetic analysis - Apparent unbound clearance of drug from plasma (CL(u)/F) of Sativex® in healthy patients and in patients with hepatic impairment(Pre-dose (0),0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 11, 24, 36 and 48 hours post dose.)
- Incidence of adverse events during the study(Days 1-7)
- Pharmacokinetic analysis - Maximum (peak) plasma concentration (Cmax) of Sativex® in healthy patients and in patients with hepatic impairment(Pre-dose (0),0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 11, 24, 36 and 48 hours post dose.)
- Pharmacokinetic analysis - Half-Life (t1/2) of Sativex® in healthy patients and in patients with hepatic impairment(Pre-dose (0),0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 11, 24, 36 and 48 hours post dose.)