ERBA: A Relative Bioavailability Study Evaluating Two New Encorafenib Formulations
Study Details
Study Description
Brief Summary
Relative bioavailability study to evaluate the pharmacokinetics of two new encorafenib formulations
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
In order to decrease the size of the current formulated encorafenib capsule and improve the physical stability, 2 new encorafenib tablet formulations have been developed.
This study is intended to select the optimal tablet formulation for commercialization based on the tablet pharmacokinetics.
A preliminary assessment of the effect of a proton-pump inhibitor on the pharmacokinetics of the 2 encorafenib tablet formulations will also be conducted to assist in the formulation selection.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Four Period Treatment Sequence: PPI Effect Participants will receive a single encorafenib dose formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the formulation after administration of 20 mg rabeprazole every evening for 5 days. |
Drug: Encorafenib capsule formulation (CAP)
A single encorafenib dose of the CAP formulation
Drug: Encorafenib first formulation
first formulation
Drug: Encorafenib second formulation
second formulation
Drug: Rabeprazole tablet
Proton-pump inhibitor
|
| Experimental: Four Period Treatment Sequence: PPI Effect Second Formulation Participants will receive a single encorafenib dose of the second formulation, a single encorafenib dose of the second formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the second formulation after administration of 20 mg rabeprazole every evening for 5 days. |
Drug: Encorafenib capsule formulation (CAP)
A single encorafenib dose of the CAP formulation
Drug: Encorafenib first formulation
first formulation
Drug: Encorafenib second formulation
second formulation
Drug: Rabeprazole tablet
Proton-pump inhibitor
|
Outcome Measures
Primary Outcome Measures
- Plasma AUCinf after administration of the first formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
Area under the plasma concentration-time profile from time zero extrapolated to infinite time
- Plasma Cmax after administration of the first formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
Maximum plasma concentration
- Plasma AUClast after administration of the first formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (Clast)
- Plasma AUCinf of the second formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
Area under the plasma concentration-time profile from time zero extrapolated to infinite time
- Plasma Cmax after administration of the second formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
Maximum plasma concentration
- Plasma AUClast after administration of the second formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (Clast)
- Plasma AUCinf after administration of the CAP (encorafenib formulated capsule) formulation [Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
Area under the plasma concentration-time profile from time zero extrapolated to infinite time
- Plasma Cmax after administration of the CAP formulation [Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
Maximum plasma concentration
- Plasma AUClast after administration of the CAP formulation [Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (Clast)
- Plasma AUCinf of the first formulation after 5 days of 20 mg daily rabeprazole dosing [Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
Area under the plasma concentration-time profile from time zero extrapolated to infinite time
- Plasma Cmax of the first formulation after 5 days of 20 mg daily rabeprazole dosing [Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
Maximum plasma concentration
- Plasma AUClast of the first formulation after 5 days of 20 mg daily rabeprazole dosing [Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (Clast)
- Plasma AUCinf of the second formulation after 5 days of 20 mg daily rabeprazole dosing [Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
Area under the plasma concentration-time profile from time zero extrapolated to infinite time
- Plasma Cmax of the second formulation after 5 days of 20 mg daily rabeprazole dosing [Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
Maximum plasma concentration
- Plasma AUClast of the second formulation after 5 days of 20 mg daily rabeprazole dosing [Day 1, Pre-dose, hour 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (Clast)
Secondary Outcome Measures
- Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time the participant provides informed consent through and including a minimum of 28 calendar days after the last administration of the study intervention.]
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. SAE is defined as one of the following: is fatal or life-threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; is medically significant; requires inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AE is defined as an AE with onset date occurring during the on-treatment period. AEs include all SAEs and non-SAEs.
- Number of Participants With Clinically Significant Change From Baseline in Vital Signs [Baseline through Period 4]
Vital signs (body temperature, respiratory rate, radial pulse, systolic and diastolic blood pressure) will be obtained with participant in the seated position, after having sat calmly for at least 5 minutes.
- Number of Participants With Electrocardiogram (ECG) Abnormalities [Baseline through Period 4 (period 4 is defined as Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48)]
ECG abnormalities criteria include a) a postdose QTcF is increased by ≥60 ms from the baseline and is >450 ms; or b) an absolute QTcF value is ≥500 ms for any scheduled ECG
- Number of Participants With Laboratory Test Abnormalities [≤ 28 days pre-dose, screening and discharge Period 1-4]
Following parameters will be analyzed for laboratory examination: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid, albumin, total protein); urinalysis.
- Time to Reach Maximum Observed Plasma Concentration (Tmax) after administration of the first formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
- Plasma Decay Half-Life (t1/2) after administration of the first formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
- Apparent Oral Clearance (CL/F) after administration of the first formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
- Apparent Volume of Distribution (Vz/F) after administration of the first formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
- Time to Reach Maximum Observed Plasma Concentration (Tmax) after administration of the second formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
- Plasma Decay Half-Life (t1/2) after administration of the second formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
- Apparent Oral Clearance (CL/F) after administration of the second formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
- Apparent Volume of Distribution (Vz/F) after administration of the second formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Periods 1-3)]
- Time to Reach Maximum Observed Plasma Concentration (Tmax) after administration of the first formulation after 5 days of 20mg daily rabeprazole dosing [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
- Plasma Decay Half-Life (t1/2) after administration of the first formulation after 5 days of 20mg daily rabeprazole dosing [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
- Apparent Oral Clearance (CL/F) after administration of the first formulation after 5 days of 20mg daily rabeprazole dosing [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
- Apparent Volume of Distribution (Vz/F) after administration of the first formulation after 5 days of 20mg daily rabeprazole dosing [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
- Time to Reach Maximum Observed Plasma Concentration Plasma after administration of the second formulation after 5 days of 20mg daily rabeprazole dosing [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
- Plasma Decay Half-Life (t1/2) after administration of the second formulation after 5 days of 20mg daily rabeprazole dosing [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
- Apparent Oral Clearance (CL/F) after administration of the second formulation after 5 days of 20mg daily rabeprazole dosing [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
- Apparent Volume of Distribution (Vz/F) after administration of the second formulation after 5 days of 20mg daily rabeprazole dosing [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 4)]
- Time to Reach Maximum Observed Plasma Concentration (Tmax) after administration of the CAP formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 1-3)]
- Plasma Decay Half-Life (t1/2) after administration of the CAP formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 1-3)]
- Apparent Oral Clearance (CL/F) after administration of the CAP formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 1-3)]
- Apparent Volume of Distribution (Vz/F) after administration of the CAP formulation [Day 1, Pre-dose, hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 (Period 1-3)]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Participants must be male or female of non-childbearing potential of 18 years of age or older, inclusive, at the time of signing the informed consent document.
-
Male and female participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
-
Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
-
Body Mass Index of 17.5 to 30.5 kg/meters squared; and a body weight >50 kg (110 lb).
-
Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent document and the protocol.
Exclusion Criteria:
-
Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease. Evidence of any active and uncontrolled bacterial or viral infection.
-
Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
-
History of human immunodeficiency virus infection, hepatitis B, or hepatitis C; positive testing for human immunodeficiency virus, Hepatitis B surface antigen, Hepatitis B core antibody or hepatitis C virus antibody. Hepatitis B vaccination is allowed.
-
Positive COVID-19 test at first admission.
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Other medical or psychiatric conditions, laboratory test abnormalities, other conditions or situations related to COVID-19 pandemic or, in the investigator's judgment, make the participant inappropriate for the study.
-
Use of prescription or non-prescription medications within 7 days prior to the first dose of encorafenib with the exception of moderate/potent CYP3A inducers which are prohibited within 14 days plus 5 half-lives prior to the first dose.
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History of known sensitivity to rabeprazole, substituted benzimidazoles or to any component of the rabeprazole formulation.
-
Previous administration with an investigational product (drug or vaccine) within 30 days.
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Known hypersensitivity to encorafenib or its excipients.
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A positive urine drug or cotinine test.
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Screening supine blood pressure ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest.
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Baseline standard 12 lead electrocardiogram that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
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Aspartate transaminase or alanine aminotransferase level ≥ 1.5 × upper limit of normal.
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Total bilirubin level ≥1.5 × upper limit of normal.
-
Estimated glomerular filtration rate <60 ml/min/1.73 m2
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | New Haven Clinical Research Unit | New Haven | Connecticut | United States | 06511 |
Sponsors and Collaborators
- Pfizer
- Ono Pharmaceutical Co. Ltd
- Pierre Fabre Laboratories
Investigators
- Study Director: Pfizer CT.gov Call Center, Pfizer
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- C4221024