Assessment of the Single Dose Pharmacokinetics and Tolerability of Sativex in Patients With Impaired Hepatic Function and Healthy Patients

NCT01887301 | Completed Phase 1

• 1 other identifier: GWCP10114
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 2

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.

Conditions

Hepatic Impairment

Outcome Measures

Primary Outcomes (3)

• Pharmacokinetic analysis - Unbound maximum plasma concentration (Cmax(u)) of Sativex® in healthy patients and in patients with hepatic impairment

  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).

  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 - 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

  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.

  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 - 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

  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.

  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.

Secondary Outcomes (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 - 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 - 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.

• 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.

Study Arms (4)

Group 1: mild hepatic impairment

ACTIVE COMPARATOR

Mild hepatic impairment: eight patients of Child-Pugh Grade A (Score 5-6). All patients received Sativex treatment.

Drug: Sativex

Group 2: Moderate hepatic impairment

ACTIVE COMPARATOR

Moderate hepatic impairment: eight patients of Child-Pugh Grade B (Score 7-9). All patients received Sativex treatment.

Drug: Sativex

Group 3: Pugh Grade B (Score 7-9).

EXPERIMENTAL

Severe hepatic impairment: eight patients of Child-Pugh Grade C (Score 10-15). All patients received Sativex treatment.

Drug: Sativex

Group 4: Control group

ACTIVE COMPARATOR

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.

Drug: Sativex

Interventions

Sativex DRUG

Patients receive four sprays (each 100 uL) of Sativex to the oral mucosa, which contain 10.8 mg THC and 10 mg CBD in total.

Also known as: Nabiximols, GW1000-02, THC/CBD spray

Group 1: mild hepatic impairment; Group 2: Moderate hepatic impairment; Group 3: Pugh Grade B (Score 7-9).; Group 4: Control group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Patients with impaired hepatic function must be compliantly on a stable dose of medication and/or treatment regimen (in the opinion of the investigator) for at least 4 weeks prior to the dosing day with no foreseeable plans for change.
• Subject is able (in the Investigators opinion) and willing to comply with all study requirements.
• Willing and able to communicate well with the Investigator.
• Subject is willing for his or her name to be notified to the responsible authorities for participation in this study, as applicable in individual countries.
• Subject is willing to allow his or her primary care practitioner and consultant, if appropriate, to be notified of participation in the study.

You may not qualify if:

• 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.
• Currently receiving a prohibited or restricted medication and unwilling to stop or comply with restriction for 14 days prior to the screening visit and for the duration of the study.
• Currently using or has used cannabis, cannabinoid-based medications (e.g. Marinol, Nabilone, Cannador), or Acomplia (rimonabant) or taranabant within 30 days of study entry and unwilling to abstain for the duration of the study.
• A known or suspected history or family history of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric disorder other than depression associated with underlying condition.
• A history of uncontrolled epilepsy as evidenced by one or more seizures in the last 12 months.
• Significant cardiac disease, e.g. has experienced myocardial infarction (MI) (if the screening ECG reveals patterns consistent with a MI and the date of the event cannot be determined, then the subject can enter the study at the discretion of the Investigator and/or local medical monitor) or clinically relevant cardiac dysfunction within the last six months, or any of the following within the last six months:

Sponsors & Collaborators

• Jazz Pharmaceuticals: lead

Study Sites (2)

Anaheim Clinical Trials, LLC

Anaheim, California, CA 92801, United States

Location

Clinical Pharmacology of Miami, Inc.

Miami, Florida, FL 33014-3616, United States

Location

MeSH Terms

Interventions

nabiximols

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 24, 2013
• First Posted: June 26, 2013
• Study Start: July 1, 2013
• Primary Completion: May 1, 2014
• Study Completion: May 1, 2014
• Last Updated: December 20, 2022

Record last verified: 2022-12

Locations

US (2)