pharmacokinetics of dabrafenib in subjects with hepatic impairment

Conditions: Hepatic Impairment

Summary: 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.

Keywords: hepatic impairment healthy volunteers clinical pharmacology study drb436 dabrafenib normal hepatic function impaired hepatic function