Clinical trial NCT02852239: Pharmacokinetics of Dabrafenib in Subjects With Renal Impairment
Official title: A Phase I, Open Label, Multicenter, Single Dose Study to Evaluate the Pharmacokinetics of Dabrafenib in Healthy Subjects With Normal Renal Function and Subjects With Impaired Renal Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Impairment
Keywords: Renal impairment
Healthy volunteers
Clinical pharmacology study
DRB436
dabrafenib
normal renal function
impaired renal function
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-08-02
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: To characterize the pharmacokinetics and safety of dabrafenib following a single 100 mg oral dose in subjects with severe renal impairment and end stage renal disease not on dialysis.

Detailed description: The main objective of this trial is to evaluate the pharmacokinetics of dabrafenib and metabolites after a single oral dose of dabrafenib in subjects with renal impairment as compared to healthy subjects with normal renal function.

This was a single-dose, open-label, parallel group single dose study to evaluate the pharmacokinetics (PK) and safety of a single oral dose of dabrafenib 100 mg in subjects with severe RI or ESRD compared to matched healthy subjects with normal renal function (control group).

The study consisted of a screening period, a treatment period and a follow-up period.

The Screening period started up to 28 days prior to dosing. Subjects who satisfied the inclusion/exclusion criteria at screening were admitted for baseline evaluations, which was done locally by the investigator. In the treatment period, subjects received a single 100 mg oral dose of dabrafenib administered as two 50 mg capsules with a whole glass of non-carbonated water (approximately 240 mL) in the morning of Day 1 following an overnight fast (minimum 10 hours). Subjects were confined to the study facility from Day -1 to Day 5, for collection of serial blood and urine samples. Subjects were discharged on Day 5.

In the follow-up period a telephone call was made to subjects 30 days post-dose to evaluate subject safety during the weeks after discharge from the facility. Adverse events occurring prior to Day 30 were followed until resolution or until judged to be permanent. Subjects returned to the clinic on Days 90 and 180 for the post-dose dermatological examination follow up.

For this study, the terms "investigational drug", "study drug" or "study treatment" refer to dabrafenib, administered as a single dose.

Eligibility criteria: Inclusion Criteria:

All subjects:

* Females must be of non-childbearing potential or must have negative pregnancy results at screening
* Good health as determined by lack of clinically significant findings
* Subjects must have a BMI between 18.0 kg/m2 and 38.0 kg/m2, with a body weight of at least 50 kg and no more than 140 kg
* Vitals signs within normal range
* Laboratory values at screening within local normal ranges or considered non-clinically significant

Additional criteria for renal impairment subjects:

-Stable renal disease without evidence of renal progression in the past 28 days prior to dosing

Additional criteria for healthy matched subjects:

* Matched to at least 1 renal impairment subject by race, age (+/-10 years), gender and weight (+/-10%)
* An absolute GFR of at least 90 ml/min

Exclusion Criteria for all subjects:

* Significant acute illness within the two weeks prior to dosing
* History or current diagnosis of cardiac disease indicating significant risk such as uncontrolled or significant cardiac disease or clinically significant ECG abnormalities
* Subjects will be screened for drugs of abuse
* History of drug or alcohol abuse within 6 months prior to dosing or evidence of such abuse as indicated by laboratory values at screening or baseline.
* Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs.
* History of malignancy of any organ system, treated or untreated, within 5 years, regardless of where there is recurrence or metastases.
* Use of drugs known to prolong the QT interval within 4 weeks prior to dosing and for the duration of the study.
* Use of drugs know to affect CYP3A4 and/or CYP2C8 including both (strong or moderate) inhibitors and inducers, within 7 days prior to dosing or during the current study are prohibited

Primary outcomes:
measure: Maximum plasma concentration (Cmax)
timeFrame: Predose through 96 hours postdose
measure: Area under the curve (AUClast)
timeFrame: Predose through 96 hours postdose
measure: Area under the curve (AUFinf)
timeFrame: Predose through 96 hours postdose
measure: Systemic drug clearance (CL/F)
timeFrame: Predose through 96 hours postdose
measure: Time to reach maximum concentration (Tmax)
timeFrame: Predose through 96 hours postdose
measure: Terminal elimination rate (Lambda_z)
timeFrame: Predose through 96 hours postdose
measure: Elimination half-life (T1/2)
timeFrame: Predose through 96 hours postdose
measure: Volume of distribution (Vz/F)
timeFrame: Predose through 96 hours postdose
measure: Unchanged drug excreted in urine (Aet)
timeFrame: Predose through 96 hours postdose
measure: Renal clearance (CLr)
timeFrame: Predose through 96 hours postdose
Secondary outcomes:
measure: Number of subjects with adverse events
timeFrame: Time of drug administration through 30 days postdose
measure: Number of subjects with abnormal lab values related to study drug
timeFrame: Time of study drug administration through 30 days postdose
measure: Number of subjects with abnormal blood pressure related to study drug
timeFrame: Time of study drug administration through 30 days postdose
measure: Changes in electrocardiogram (ECG)
timeFrame: Time of study drug administration through 30 days postdose
measure: Number of subjects with abnormal pulse rate related to study drug
timeFrame: Time of study drug administration through 30 days postdose
measure: Number of subjects with abnormal respiratory rate related to study drug
timeFrame: Time of study drug administration through 30 days postdose
Other outcomes:
Locations:
city: DeBary
country: United States
facility: Omega Research Consultants LLC
state: Florida
city: Berlin
country: United States
facility: Hassman Research Institute
state: New Jersey
city: Raleigh
country: United States
facility: Wake Research Associates Oncology
state: North Carolina
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: