Pharmacokinetics of Dabrafenib in Subjects With Hepatic Impairment

A Phase I, Open Label, Multicenter, Single Dose Study to Evaluate the Pharmacokinetics of Dabrafenib in Healthy Subjects With Normal Hepatic Function and Subjects With Impaired Hepatic Function

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

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.