Pharmacokinetics of Dabrafenib in Subjects With Hepatic Impairment

Novartis

Status and phase: Terminated; Phase 1

Conditions: Hepatic Impairment

Treatments: Drug: dabrafenib

Study type: Interventional

Funder types: Industry

Identifiers

NCT02873650

CDRB436A2107

Details and patient eligibility

About

To characterize the pharmacokinetics and safety of dabrafenib following a single 100 mg oral dose in subjects with moderate and severe hepatic impairment.

Enrollment: 5 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Inclusion criteria (for all subjects)

• Male and/or female subjects 18-75 years of age
• Females must be of non-childbearing potential . All non-postmenopausal females must have a confirmed negative serum pregnancy
• Subjects in good health condition as determined by no clinically significant findings from medical history and physical examination.
• Body mass index (BMI) between ≥18.0 and ≤38.0 kg/m2, with body weight ≥ 50 kg and no more than 140 kg
• Laboratory values must be within normal limits (correction allowed) or considered clinically insignificant
• Do not participate in any other clinical trials with a BRAF or other RAF inhibitors

Additional inclusion criteria for patients with normal hepatic function (Control group):

• Absence of clinically significant deviation from normal in medical history, physical examination, vital signs, electrocardiograms and clinical laboratory determinations.
• Must match to at least one hepatic impairment subject by age, gender and bodyweight

Additional inclusion criteria for hepatic impaired subjects:

• Confirmed hepatic disease
• Stable Child-Pugh status within 28 days prior to dosing.

Exclusion criteria for all subjects

• Participation in any clinical investigation within 4 weeks prior to dosing
• Significant acute illness within the two weeks prior to dosing
• History of immunodeficiency diseases, including a positive HIV
• History of malignancy of any organ system, treated or untreated, within 5 years
• Any prior history of keratoacanthoma and/or cutaneous squamous cell carcinoma
• A known diagnosis of any of the RASopathies, such as NF-1, Noonan syndrome, or related conditions.
• History of drug or alcohol abuse within the 6 months prior to dosing
• Smoking: urine cotinine levels below 500 ng/mL on Day -1.
• Use of drugs known to affect CYP3A4 and/or CYP2C8 including both (strong or moderate) inhibitors and inducers, within 7 days prior to dosing
• Administration of medications that prolong the QT interval within 4 weeks prior to dosing and until EOT.
• History or current diagnosis of cardiac disease indicating significant risk of safety
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs.

Additional exclusion criteria for healthy subjects (control group):

• Clinical evidence of liver disease or liver injury
• History or presence of renal impairment as indicated by abnormal creatinine or BUN values
• A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody

Additional exclusion criteria for subjects with hepatic impairment:

• Alcohol or drug abuse within one month prior to dosing or evidence of such
• History of liver transplantation at any time in the past and is on immunosuppressant therapy.
• Encephalopathy Grade 3 or worse within 28 days of dosing.
• History of surgical portosystemic shunt.
• Life expectancy ≤3 months

Other protocol-defined inclusion/exclusion may apply.

Trial design

Primary purpose: Basic Science

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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5 participants in 3 patient groups

Group 1 - Control group

Experimental group

Treatment:

Drug: dabrafenib

Group 2-Moderate hepatic impairment

Experimental group

Treatment:

Drug: dabrafenib

Group 3-Severe hepatic impairment

Experimental group

Treatment:

Drug: dabrafenib