Bioequivalence Binimetinib 3 x 15 mg and 45 mg Formulations
- Conditions
- Unresectable MelanomaMetastatic MelanomaMelanomaBRAF V600 Mutation
- Interventions
- Registration Number
- NCT05810740
- Lead Sponsor
- Pierre Fabre Medicament
- Brief Summary
The current commercially available MEKTOVI® (binimetinib) 15 mg tablets are provided as immediate release film-coated tablets for oral administration. For the treatment of adult patients with unresectable or metastatic melanoma with BRAF V600 mutation, the recommended dosing regimen is 45 mg twice daily (bis in die, BID). No food effect with the commercial formulation of 15 mg was demonstrated. In order to reduce the patient's burden, a new strength tablet containing 45 mg of binimetinib as active ingredient is being developed. As a result, the number of tablets to be taken by the patients will be reduced from 6 tablets (6 x 15 mg) to 2 tablets (2 x 45 mg) per day. The evaluation of the bioequivalence between one 45 mg tablet and three 15 mg tablets is therefore required.
- Detailed Description
The reference (R) formulation is the currently commercially available tablet containing 15 mg of binimetinib as active substance, administered as three tablets for a total of 45 mg binimetinib. The Test (T) formulation is the tablet containing 45 mg of binimetinib as active substance in one tablet. Participants will be randomized to one of 2 treatment sequences (RT or TR) containing 2 treatment periods, with at least a 7-day washout between each dose.
The study will consist of a screening period between 21 and 2 days before the first study treatment administration on Period (P) 1 Day (D) 1, 2 treatment periods of 5 days each, and a washout of at least 7 days between P1D1 and P2D1.
Study treatments are given by the oral route in fasted condition. The end-of-study (EOS) visit will be performed 30 (± 3) days after the last study treatment administration or discontinuation.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 37
- Healthy participant.
- Female participants must be postmenopausal or sterilized.
- Body mass index (BMI) of ≥ 18.5 to < 30 kg/m2, with body weight ≥ 50 kg and < 100 kg.
- Vital signs within defined ranges or if out of normal ranges, considered as not clinically significant by the Investigator.
- Participants must have safety laboratory values within the normal ranges or if out of normal ranges considered as not clinically significant by the Investigator.
-
Pregnant or currently breastfeeding women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
-
A past medical history of clinically significant ECG abnormalities or a family history (grandparents, parents, and siblings) of prolonged QT interval syndrome.
-
Impaired cardiovascular function.
-
History of fainting spells or orthostatic hypotension episodes.
-
Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs or which may jeopardize the participant in case of participation in the study.
-
History of autonomic dysfunction or Gilbert syndrome.
-
History or current evidence of Central serous retinopathy (CSR), Retinal vein occlusion (RVO) or ophthalmopathy as assessed by ophthalmologic examination at baseline that would be considered a risk factor for CSR/RVO [e.g., optic disc cupping, visual field defects, intraocular pressure (IOP) > 21 mmHg].
-
Neuromuscular disorders that were associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
-
Smoker or use of tobacco products or products containing nicotine in the last 4 weeks prior to first dosing of study treatment.
-
Malignancy with the following exceptions:
- Adequately treated basal cell or squamous cell carcinoma of the skin (adequate wound healing is required prior to study entry).
- Primary malignancy which had been completely resected and was in complete remission for ≥ 5 years.
-
History of retinal degenerative disease.
-
Any vaccination within 4 weeks prior to dosing.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Binimetinib 15 mg then Binimetinib 45 mg Binimetinib 15 MG Participants first received a single dose of 3 tablets of Binimetinib 15 mg orally in fasted conditions in the morning on day 1 of a 5-day period. After a washout period of 7 days, they then received a single dose of 1 tablet of Binimetinib 45 mg orally in fasted conditions in the morning for five days on day 1 of a second 5-day period. Binimetinib 15 mg then Binimetinib 45 mg Binimetinib 45 MG Participants first received a single dose of 3 tablets of Binimetinib 15 mg orally in fasted conditions in the morning on day 1 of a 5-day period. After a washout period of 7 days, they then received a single dose of 1 tablet of Binimetinib 45 mg orally in fasted conditions in the morning for five days on day 1 of a second 5-day period. Binimetinib 45 mg then Binimetinib 15 mg Binimetinib 15 MG Participants first received a single dose of 1 tablet of Binimetinib 45 mg orally in fasted conditions in the morning on day 1 of a 5-day period. After a washout period of 7 days, they then received a single dose of 3 tablets of Binimetinib 15 mg orally in fasted conditions in the morning for five days on day 1 of a second 5-day period. Binimetinib 45 mg then Binimetinib 15 mg Binimetinib 45 MG Participants first received a single dose of 1 tablet of Binimetinib 45 mg orally in fasted conditions in the morning on day 1 of a 5-day period. After a washout period of 7 days, they then received a single dose of 3 tablets of Binimetinib 15 mg orally in fasted conditions in the morning for five days on day 1 of a second 5-day period.
- Primary Outcome Measures
Name Time Method Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for Binimetinib Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUClast is defined as area under the concentration from zero to the last quantifiable plasma concentration.
AUC From Time of Administration to Infinity (AUCinf) for Binimetinib Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUCinf is defined as Area under the plasma concentration-time curve from time of administration to infinity
Maximum Observed Plasma Concentration (Cmax) for Binimetinib Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Cmax,norm is defined as Cmax divided by dose (mg) per kg body weight.
- Secondary Outcome Measures
Name Time Method Time to Reach Cmax (Tmax) for Binimetinib Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Terminal Half-life (t1/2) for Binimetinib Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose The apparent terminal elimination half-life (t½) is defined as the time necessary for the concentration of a drug to decrease by one-half in the terminal phase
First Order Terminal Elimination Rate Constant (λz) of Binimetinib Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose The first Order Terminal Elimination Rate Constant (λz) of Binimetinib corresponds to the rate at which a drug is removed from the human system
Residual Area (AUC_%Extrap_obs) for Binimetinib Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose The residual area under the curve is expressed as a percentage of the total AUC extrapolated from tz to ∞, based on the area under the concentration-time curve.
Mean Residence Time (MRT) for Binimetinib Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose Mean residence time (MRT) is defined as the average time for binimetinib to reside in the body
Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for AR00426032 Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUClast is defined as area under the concentration from zero to the last quantifiable plasma concentration of AR00426032, a metabolite of binimetinib
AUC From Time of Administration to Infinity (AUCinf) for AR00426032 Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUCinf is defined as Area under the plasma concentration-time curve from time of administration to infinity of AR00426032, a metabolite of binimetinib
Maximum Observed Plasma Concentration (Cmax) for AR00426032 Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose Cmax is referred as the maximum observed concentration of AR00426032 in blood plasma determined by bioanalysis
Time to Reach Cmax (Tmax) for AR00426032 Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose The timepoint at which the maximum concentration of AR00426032 is determined by bioanalysis in the blood plasma
Terminal Half-life (t1/2) for AR00426032 Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose The apparent terminal elimination half-life (t½) is defined as the time necessary for the concentration of a drug to decrease by one-half in the terminal phase
First Order Terminal Elimination Rate Constant (λz) of AR00426032 Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose The first Order Terminal Elimination Rate Constant (λz) of AR00426032 corresponds to the rate at which a drug is removed from the human system
Mean Residence Time (MRT) for AR00426032 Pre-dose = 0h and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post dose Mean residence time (MRT) is defined as the average time for AR00426032 to reside in the body
Clinically Significant Changes From Baseline of Blood Hematology Parameters Blood samples for hematology parameters were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at end of study (EOS) Clinically significant shift from baseline in blood hematology parameters (Erythrocytes (red blood cells, RBC), hematocrit, hemoglobin, platelets; leukocyte count with differential: basophils, eosinophils, lymphocytes, monocytes, neutrophils/absolute neutrophil count; RBC indices: mean corpuscular hemoglobin, mean corpuscular volume, reticulocytes/erythrocytes.)
Clinically Significant Changes From Baseline of Clinical Chemistry Parameters Blood samples for clinical chemistry parameters were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at EOS Clinically significant shift from baseline in clinical chemistry parameters (alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin, gamma glutamyl transferase (GGT), indirect bilirubin, creatinine, urea, bicarbonate, calcium, chloride, magnesium, potassium, sodium, glucose, cholesterol, urate, albumin, creatine kinase (CK), lactate dehydrogenase, protein, amylase, and lipase)
Clinically Significant Changes From Baseline of Coagulation Parameters Blood samples for coagulation parameters were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at EOS Clinically significant shifts from baseline in coagulation parameters (activated partial thromboplastin time and prothrombin time)
Clinically Significant Changes From Baseline of Urinalysis Parameters Urinalysis samples were taken at screening, on Day -1 of each period, at H24 and H48 post-dose of each period, and at EOS Clinically significant changes from baseline in the quantitative assessment of pH, bilirubin, erythrocytes, glucose, ketones, leukocyte esterase, nitrite, protein, and urobilinogen
Clinically Significant Abnormalities Values of Vital Sign Parameters Vital signs were measured at screening, on Day -1 of each period, at Day 1 pre-dose, H24 and H72 post-dose of each period, and at EOS Number of participants with at least one clinically significant vital signs abnormality. The following clinical signs were measured: supine and standing systolic and diastolic blood pressure (mmHg), pulse rate (beats/min) body temperature (°C), body weight, and BMI
Clinically Significant Orthostatic Hypotension Vital signs were measured at screening, on Day -1 of each period, at Day 1 pre-dose, H24 and H72 post-dose of each period, and at EOS The number and percentage of participants with at least one orthostatic hypotension defined as standing systolic blood pressure (SBP) - supine SBP ≤ -20 mmHg or standing diastolic blood pressure (DBP) - supine DBP ≤ -10 mmHg considered clinically significant.
Clinically Significant Abnormalities Values in 12-lead Electrocardiograms (ECG) ECG abnormalities were recorded in triplicate at screening, on Day -1 of each period, at Day 1 pre-dose and H24 post-dose of each period, and at EOS Number of participant with at least one clinically significant electrocardiogram abnormality. The following standard 12-lead ECG parameters were recorded: heart rate (beats/min), PR interval (msec), QRS duration (msec), QRS axis (deg), QT interval (msec) and Fridericia QTc interval (msec)
Clinically Significant Physical Examination Abnormalities A complete physical examination was performed at screening, on Day -1 of each period, at H24 post-dose of each period, and at EOS Number of participants with at least one clinically significant physical examination abnormality. A complete physical examination, including at minima assessments of the cardiovascular, dermatological, ear/nose/throat, eyes, gastrointestinal, general health/overall appearance, head, lymph, musculoskeletal, neck, neurological, and respiratory systems was performed
Abnormal Changes From Baseline in Visual Examinations A visual examination was performed at Screening at at EOS. Visual assessment was performed at screening, on Day -1 of each period, at H24 and H72 post-dose of each period, and at EOS
Abnormal Changes From Baseline in Ophthalmologic Examinations An opthalmologic examination was performed at Screening at at EOS. Abnormal changes from baseline in ophthalmologic examinations including best corrected visual acuity for distance testing, optical coherence tomography and/or fluorescein angiography, slit lamp examination, IOP and dilated fundoscopy with attention to retinal abnormalities
Trial Locations
- Locations (1)
Biotrial
🇫🇷Rennes, France