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Pharmacokinetics of Dabrafenib in Subjects With Renal Impairment

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ClinicalTrials.gov Identifier: NCT02852239
Recruitment Status : Completed
First Posted : August 2, 2016
Last Update Posted : July 9, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
Renal Impairment Drug: dabrafenib Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
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
Actual Study Start Date : December 19, 2016
Actual Primary Completion Date : September 27, 2019
Actual Study Completion Date : September 27, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Dabrafenib

Arm Intervention/treatment
Experimental: Group 1 - Normal renal function
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.
Drug: dabrafenib
Single dose dabrafenib 100 mg
Other Name: DRB436

Experimental: Group 2 - Severe renal function
Subjects with severe renal impairment defined as GFR of 15-29 mL/min at baseline.
Drug: dabrafenib
Single dose dabrafenib 100 mg
Other Name: DRB436

Experimental: Group 3 - End stage renal disease (ESRD)
Subjects with end stage renal disease (ESRD), defined as GFR of <15 mL/min at baseline.
Drug: dabrafenib
Single dose dabrafenib 100 mg
Other Name: DRB436




Primary Outcome Measures :
  1. Maximum plasma concentration (Cmax) [ Time Frame: Predose through 96 hours postdose ]
    The maximum (peak) observed plasma drug concentration after a single dose of dabrafenib

  2. Area under the curve (AUClast) [ Time Frame: Predose through 96 hours postdose ]
    AUClast is the area under the curve calculated to the last quantifiable concentration point after a single dose of dabrafenib

  3. Area under the curve (AUFinf) [ Time Frame: Predose through 96 hours postdose ]
    AUCinf is the area under the plasma concentration time curve extrapolated to infinity after a single dose of dabrafenib

  4. Systemic drug clearance (CL/F) [ Time Frame: Predose through 96 hours postdose ]
    Systemic clearance from plasma of dabrafenib after a single dose

  5. Time to reach maximum concentration (Tmax) [ Time Frame: Predose through 96 hours postdose ]
    The time to reach maximum (peak) concentration of dabrafenib after a single dose

  6. Terminal elimination rate (Lambda_z) [ Time Frame: Predose through 96 hours postdose ]
    Terminal elimination rate of dabrafenib after a single dose

  7. Elimination half-life (T1/2) [ Time Frame: Predose through 96 hours postdose ]
    Elimination half-life of dabrafenib after a single dose

  8. Volume of distribution (Vz/F) [ Time Frame: Predose through 96 hours postdose ]
    The apparent volume of distribution during the terminal elimination phase of dabrafenib after a single dose

  9. Unchanged drug excreted in urine (Aet) [ Time Frame: Predose through 96 hours postdose ]
    The amount of unchanged dabrafenib excreted in urine after a single dose

  10. Renal clearance (CLr) [ Time Frame: Predose through 96 hours postdose ]
    Renal clearance of dabrafenib calculated using plasma AUC after a single dose


Secondary Outcome Measures :
  1. Number of subjects with adverse events [ Time Frame: Time of drug administration through 30 days postdose ]
    Assess the safety of a single dose of dabrafenib through AE reports of subjects from drug administration through 30 days postdose

  2. Number of subjects with abnormal lab values related to study drug [ Time Frame: Time of study drug administration through 30 days postdose ]
    Assess the safety of a single dose of dabrafenib through hematology and chemistry blood tests

  3. Number of subjects with abnormal blood pressure related to study drug [ Time Frame: Time of study drug administration through 30 days postdose ]
    Assess the safety of a single dose of dabrafenib by monitoring changes in blood pressure

  4. Changes in electrocardiogram (ECG) [ Time Frame: Time of study drug administration through 30 days postdose ]
    Assess the safety of a single dose of dabrafenib by monitoring changes in ECG

  5. Number of subjects with abnormal pulse rate related to study drug [ Time Frame: Time of study drug administration through 30 days postdose ]
    Assess the safety of a single dose of dabrafenib by monitoring changes in heart rate

  6. Number of subjects with abnormal respiratory rate related to study drug [ Time Frame: Time of study drug administration through 30 days postdose ]
    Assess the safety of a single dose of dabrafenib by monitoring changes in respiratory rate



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02852239


Locations
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United States, Florida
Omega Research Consultants LLC
DeBary, Florida, United States, 32713
United States, New Jersey
Hassman Research Institute
Berlin, New Jersey, United States, 08009
United States, North Carolina
Wake Research Associates Oncology
Raleigh, North Carolina, United States, 27612
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Additional Information:
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02852239    
Other Study ID Numbers: CDRB436A2106
First Posted: August 2, 2016    Key Record Dates
Last Update Posted: July 9, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Renal impairment
Healthy volunteers
Clinical pharmacology study
DRB436
dabrafenib
normal renal function
impaired renal function
Additional relevant MeSH terms:
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Renal Insufficiency
Kidney Diseases
Urologic Diseases
Dabrafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action