Effect of Moderate Hepatic Impairment on the Pharmacokinetics and Metabolism of a Single Dose of Licarbazepine

• Register: ClinicalTrials.gov
• Last refreshed on: 19 February 2015
• Main ID: NCT00424671
• Date of registration: 18/01/2007
• Prospective Registration: No
• Primary sponsor: Novartis
• Public title: Effect of Moderate Hepatic Impairment on the Pharmacokinetics and Metabolism of a Single Dose of Licarbazepine
• Scientific title: An Open-Label Study in Healthy Subjects and in Subjects With Stable Impaired Hepatic Function to Assess the Effect of Moderate Hepatic Impairment on Licarbazepine Pharmacokinetics and Metabolism After a Single Dose of 1000 mg Licarbazepine IR Tablets
• Date of first enrolment: November 2006
• Target sample size: 16
• Recruitment status: Completed
• URL: http://clinicaltrials.gov/show/NCT00424671
• Study type: Interventional
• Study design: Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
• Phase: Phase 1

Countries of recruitment

Czech Republic

Contacts

• Name: Novartis
• Affiliation: Investigative site

Key inclusion & exclusion criteria

Inclusion Criteria:

Control group and hepatically impaired groups:

- Male and/or female subjects between 18 and 65 years of age. Female subjects must be
surgically sterilized or postmenopausal (Postmenopausal women must have no regular
menstrual bleeding for at least 2 years prior to inclusion. Menopause will be
confirmed by a plasma FSH level of >40 IU/L. Female subjects must have been
surgically sterilized at least 6 months prior to screening. Surgical sterilization
procedures must be supported with clinical documentation made available to sponsor
and noted in the Relevant Medical History / Current Medical Conditions section of the
CRF)

- Able to communicate well with the investigator, to understand and comply with the
requirements of the study. The subjects must be able to provide written informed
consent prior to study participation, thus excluding subjects with encephalopathy
grade 3 or 4.

- Body mass index (BMI) must be within the range of 18 to 32. For instructions and
tables see Appendix 5.

Hepatically impaired group:

- Subjects must have liver cirrhosis (hepatic fibrosis with evidence of either micro-
or macro-nodular regeneration) confirmed by imaging techniques, ultrasound, MRI or
CT.

- Subjects must have physical signs consistent with a clinical diagnosis of liver
cirrhosis (e.g., liver firmness to palpation, splenic enlargement, spider angiomata,
palmar erythema, parotid hypertrophy, testicular atrophy, gynecomastia).

- Subjects must have a Child-Pugh Clinical Assessment Score between 7 and 9 at both
screening and baseline.

- Vital signs (after 3 minutes resting in a supine position) which are within the
following ranges: oral body temperature between 35.0-37.5 °C systolic blood pressure,
100-180 mm Hg diastolic blood pressure, 60-115 mm Hg pulse rate, 60 - 100 bpm

- Subjects with creatinine clearance greater than 50 mL/min (based on Cockcroft and
Gault formula)

Control group:

- Subjects must be in good health as determined by past medical history, physical
examination, vital signs, electrocardiogram, and laboratory tests at screening.

- Subjects should be matched to the hepatically impaired group in gender, age (±10%),
smoking status, BMI (±10%).

- At Screening, and Baseline, vital signs (systolic and diastolic blood pressure and
pulse rate) will be assessed after the subject has rested for at least three (3)
minutes, and again when required after three (3) minutes in the standing position.
Vital signs should be within the following ranges: oral body temperature between
35.0-37.5 °C systolic blood pressure, 90-140 mm Hg diastolic blood pressure, 50-90 mm
Hg pulse rate, 40 - 90 bpm When blood pressure and pulse will be taken again after 3
minutes standing, there shall be no more than a 20 mm Hg drop in systolic or 10 mm Hg
drop in diastolic blood pressure and increase in heart rate (>20 bpm) associated with
clinical manifestation of postural hypotension. All blood pressure measurements at
other time-points should be assessed with the subject supine, unless stated otherwise
in the protocol design, and utilizing the same arm for each determination.

Exclusion Criteria:

Control group and hepatically impaired group:

- Participation in any clinical investigation with experimental drug therapy within
four weeks prior to dosing or longer as required by local regulation.

- Donation or loss of 400 mL or more of blood within two months prior to dosing.

- Significant acute, new onset illness (ie, flu, gastroenteritis) within two weeks
prior to dosi4. A past medical history or clinically significant ECG abnormalities or
a family history (grandparents, parents and siblings) of a prolonged QT-interval
syndrome.

- History of hyponatremia or seizures.

- History of autonomic dysfunction.

- Subjects with a consistent, abnormally low total lymphocyte count (< 10% of total
white blood cell counts)

- A known hypersensitivity to the drug.

- History of immunocompromise, including a positive HIV (ELISA and Western blot) test
result.

- Evidence of active alcohol or drug abuse as indicated by the laboratory assays
conducted during the screening or baseline evaluations.

- Smokers who report cigarette use of more than 20 cigarettes per day. Urine cotinine
levels will be measured during screening.

Hepatically impaired group:

- Subjects with a history of unstable, severe, or clinically significant cardiovascular
disease

- Polymorphonuclears <1000/µL or platelets <100’000/µL at inclusion.

- Subjects with clinically significant abnormal findings, not consistent with
underlying disease, upon physical examination, ECG or laboratory evaluation.

- Subjects with frank symptoms of encephalopathy or ataxia.

- A recent history of acute or chronic bronchospastic disease, including asthma and
chronic obstructive pulmonary disease, treated or not treated.

- Any surgical or medical condition which might significantly alter the absorption,
distribution, or excretion of any drug.

- Current drug treatment with other mood stabilizers, psychotropic drugs and
antiepileptics.

Patients must be willing and able to forgo treatment with restricted medications
throughout the study. Approved prescription medications will be allowed during the course
of the study on a case by case basis only if the patient has been on a standard treatment
regimen for at least 3 months and will continue their regular regimen without change
throughout the study (unless required by protocol or to treat an adverse event) Treatments
in table 5.1 are allowed in the hepatically impaired group only.

Control group

- Use of any prescription medication within 1 month prior to dosing.

- Use of over-the-counter medications or vitamins during 14 days prior to dosing
(Paracetamol, aspirin or ibuprofen are acceptable, but must be documented in the
CRF).

- History or presence of liver disease or liver injury as indicated by an abnormal
liver function profile such as SGOT, SGPT, GGT, alkaline phosphate, or serum
bilirubin.

- Hepatitis B as indicated by positive HBs Ag or positive anti-HBc IgM result, or
Hepatitis C as indicated by positive anti-HCV result.

- History of acute or chronic bronchospastic disease, including asthma and chronic
obstructive pulmonary disease, treated or not treated.

- Any surgical or medical condi


Age minimum: 18 Years
Age maximum: 65 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Healthy

Intervention(s)

Drug: Licarbazepine

Primary Outcome(s)

Influence of moderate hepatic impairment on the pharmacokinetics of

licarbazepine after single oral administration of 1000 mg licarbazepine (given as 2 x 500

mg IR tablets) in healthy subjects and in moderate hepatic impaired subjects

Secondary Outcome(s)

Safety and tolerability of single oral doses of 1000 mg licarbazepine (given

500 mg IR tablets) in healthy subjects and in moderate hepatic impaired subjects

two enantiomers after single oral administration of 1000 mg licarbazepine (given as 2 x

as 2 x 500 mg IR tablets) in healthy subjects and in moderate hepatic impaired subjects

Influence of moderate hepatic impairment on the pharmacokinetics of the two enantiomers of licarbazepine and the glucuronide conjugates of licarbazepine and its

Secondary ID(s)

CLIC477D2310

Source(s) of Monetary Support

Please refer to primary and secondary sponsors