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Pharmacokinetics of Dabrafenib in Subjects With Renal Impairment

Primary Purpose

Renal Impairment

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

dabrafenib

About this trial

This is an interventional basic science trial for Renal Impairment focused on measuring Renal impairment, Healthy volunteers, Clinical pharmacology study, DRB436, dabrafenib, normal renal function, impaired renal function

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Omega Research Consultants LLC
Hassman Research Institute
Wake Research Associates Oncology

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Group 1 - Normal renal function

Group 2 - Severe renal function

Group 3 - End stage renal disease (ESRD)

Arm Description

Subjects with normal renal function defined as GFR ≥ 90 mL/min at baseline and matching to the renal impaired subject based on gender, race, age, and weight.

Subjects with severe renal impairment defined as GFR of 15-29 mL/min at baseline.

Subjects with end stage renal disease (ESRD), defined as GFR of <15 mL/min at baseline.

Outcomes

Primary Outcome Measures

Maximum plasma concentration (Cmax)

The maximum (peak) observed plasma drug concentration after a single dose of dabrafenib

Area under the curve (AUClast)

AUClast is the area under the curve calculated to the last quantifiable concentration point after a single dose of dabrafenib

Area under the curve (AUFinf)

AUCinf is the area under the plasma concentration time curve extrapolated to infinity after a single dose of dabrafenib

Systemic drug clearance (CL/F)

Systemic clearance from plasma of dabrafenib after a single dose

Time to reach maximum concentration (Tmax)

The time to reach maximum (peak) concentration of dabrafenib after a single dose

Terminal elimination rate (Lambda_z)

Terminal elimination rate of dabrafenib after a single dose

Elimination half-life (T1/2)

Elimination half-life of dabrafenib after a single dose

Volume of distribution (Vz/F)

The apparent volume of distribution during the terminal elimination phase of dabrafenib after a single dose

Unchanged drug excreted in urine (Aet)

The amount of unchanged dabrafenib excreted in urine after a single dose

Renal clearance (CLr)

Renal clearance of dabrafenib calculated using plasma AUC after a single dose

Secondary Outcome Measures

Number of subjects with adverse events

Assess the safety of a single dose of dabrafenib through AE reports of subjects from drug administration through 30 days postdose

Number of subjects with abnormal lab values related to study drug

Assess the safety of a single dose of dabrafenib through hematology and chemistry blood tests

Number of subjects with abnormal blood pressure related to study drug

Assess the safety of a single dose of dabrafenib by monitoring changes in blood pressure

Changes in electrocardiogram (ECG)

Assess the safety of a single dose of dabrafenib by monitoring changes in ECG

Number of subjects with abnormal pulse rate related to study drug

Assess the safety of a single dose of dabrafenib by monitoring changes in heart rate

Number of subjects with abnormal respiratory rate related to study drug

Assess the safety of a single dose of dabrafenib by monitoring changes in respiratory rate

Full Information

NCT ID

NCT02852239

First Posted

July 26, 2016

Last Updated

December 6, 2020

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT02852239

Brief Title

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

2. Study Status

Record Verification Date

July 2020

Overall Recruitment Status

Completed

Study Start Date

December 19, 2016 (Actual)

Primary Completion Date

September 27, 2019 (Actual)

Study Completion Date

September 27, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Renal Impairment

Keywords

Renal impairment, Healthy volunteers, Clinical pharmacology study, DRB436, dabrafenib, normal renal function, impaired renal function

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

22 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group 1 - Normal renal function

Arm Type

Experimental

Arm Description

Subjects with normal renal function defined as GFR ≥ 90 mL/min at baseline and matching to the renal impaired subject based on gender, race, age, and weight.

Arm Title

Group 2 - Severe renal function

Arm Type

Experimental

Arm Description

Subjects with severe renal impairment defined as GFR of 15-29 mL/min at baseline.

Arm Title

Group 3 - End stage renal disease (ESRD)

Arm Type

Experimental

Arm Description

Subjects with end stage renal disease (ESRD), defined as GFR of <15 mL/min at baseline.

Intervention Type

Drug

Intervention Name(s)

dabrafenib

Other Intervention Name(s)

DRB436

Intervention Description

Single dose dabrafenib 100 mg

Primary Outcome Measure Information:

Title

Maximum plasma concentration (Cmax)

Description

The maximum (peak) observed plasma drug concentration after a single dose of dabrafenib

Time Frame