Pharmacokinetics of Dabrafenib in Subjects With Hepatic Impairment

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


Eligibility 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.