Pharmacokinetics of Dabrafenib in Subjects With Hepatic Impairment

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

Official Title
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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

Conditions
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Hepatic Impairment

Intervention / Treatment
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* Drug: dabrafenib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: open-label, parallel group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - Control group<br> | Drug: dabrafenib<br>* Single dose of 100 mg dabrafenib on Day 1<br>* Other names: DRB436;|
| Experimental: Group 2-Moderate hepatic impairment<br> | Drug: dabrafenib<br>* Single dose of 100 mg dabrafenib on Day 1<br>* Other names: DRB436;|
| Experimental: Group 3-Severe hepatic impairment<br> | Drug: dabrafenib<br>* Single dose of 100 mg dabrafenib on Day 1<br>* Other names: DRB436;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) |  | Predose through 96 hours postdose | 
| Area under the curve (AUClast) |  | Predose through 96 hours postdose | 
| Area under the curve (AUFinf) |  | Predose through 96 hours postdose | 
| Systemic drug clearance (CL/F) |  | Predose through 96 hours postdose | 
| Time to reach maximum concentration (Tmax) |  | Predose through 96 hours postdose | 
| Terminal elimination rate (Lambda_z) |  | Predose through 96 hours postdose | 
| Elimination half-life (T1/2) |  | Predose through 96 hours postdose | 
| Volume of distribution (Vz/F) |  | Predose through 96 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events |  | Time of study drug administration through 30 days postdose | 
| Number of subjects with abnormal lab values related to study drug |  | Time of study drug administration through 30 days postdose | 
| Number of subjects with abnormal blood pressure related to study drug |  | Time of study drug administration through 30 days postdose | 
| Number of subjects with abnormal pulse rate related to study drug |  | Time of study drug administration through 30 days postdose | 
| Number of subjects with abnormal respiratory rate related to study drug |  | Time of study drug administration through 30 days postdose | 
| Number of subjects with abnormal body temperature related to study drug |  | Time of study drug administration through 30 days postdose | 
| Changes in electrocardiogram (ECG) |  | Time of study drug administration through 30 days postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatic impairment, Healthy volunteers, Clinical pharmacology study, DRB436, dabrafenib, normal hepatic function, impaired hepatic function