Phase 1
Completed N=37
Bioequivalence Binimetinib 3 x 15 mg and 45 mg Formulations
Melanoma · BRAF V600 Mutation · Unresectable Melanoma
Source: ClinicalTrials.gov NCT05810740 ↗
Enrolled (actual)
37
Serious AEs
0.0%
Results posted
Sep 2024
Primary outcomePrimary: Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for Binimetinib — 1786; 1723 h*ng/mL
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for Binimetinib |
1786; 1723 | — |
| PRIMARY AUC From Time of Administration to Infinity (AUCinf) for Binimetinib |
1834; 1784 | — |
| PRIMARY Maximum Observed Plasma Concentration (Cmax) for Binimetinib |
388.0; 362.2 | — |
| SECONDARY Time to Reach Cmax (Tmax) for Binimetinib |
1.0000; 0.7500 | — |
| SECONDARY Terminal Half-life (t1/2) for Binimetinib |
13.002; 13.901 | — |
| SECONDARY First Order Terminal Elimination Rate Constant (λz) of Binimetinib |
0.05331; 0.04986 | — |
| SECONDARY Residual Area (AUC_%Extrap_obs) for Binimetinib |
2.2836; 2.8499 | — |
| SECONDARY Mean Residence Time (MRT) for Binimetinib |
11.67; 12.588 | — |
| SECONDARY Area Under the Plasma Concentration-time Curve (AUC) From Time of Administration to Last Observed Plasma Concentration (AUClast) for AR00426032 |
223.9; 213.5 | — |
| SECONDARY AUC From Time of Administration to Infinity (AUCinf) for AR00426032 |
296.8; 287.5 | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) for AR00426032 |
41.62; 37.88 | — |
| SECONDARY Time to Reach Cmax (Tmax) for AR00426032 |
1.1250; 1.000 | — |
| SECONDARY Terminal Half-life (t1/2) for AR00426032 |
13.924; 13.843 | — |
| SECONDARY First Order Terminal Elimination Rate Constant (λz) of AR00426032 |
0.04978; 0.05007 | — |
| SECONDARY Mean Residence Time (MRT) for AR00426032 |
14.900; 14.952 | — |
| SECONDARY Clinically Significant Changes From Baseline of Blood Hematology Parameters |
0; 0 | — |
| SECONDARY Clinically Significant Changes From Baseline of Clinical Chemistry Parameters |
0; 0 | — |
| SECONDARY Clinically Significant Changes From Baseline of Coagulation Parameters |
0; 0 | — |
| SECONDARY Clinically Significant Changes From Baseline of Urinalysis Parameters |
0; 0 | — |
| SECONDARY Clinically Significant Abnormalities Values of Vital Sign Parameters |
0; 0 | — |
| SECONDARY Clinically Significant Orthostatic Hypotension |
0; 1 | — |
| SECONDARY Clinically Significant Abnormalities Values in 12-lead Electrocardiograms (ECG) |
0; 0 | — |
| SECONDARY Clinically Significant Physical Examination Abnormalities |
0; 0 | — |
| SECONDARY Abnormal Changes From Baseline in Visual Examinations |
0; 0 | — |
| SECONDARY Abnormal Changes From Baseline in Ophthalmologic Examinations |
1; 0 | — |
Eligibility Criteria
Inclusion criteria
All the following inclusion criteria had to be met for a participant to be eligible to be included in this study:
- Provide a signed and dated ICF.
- Healthy participant. Note: defined as an absence of clinically significant abnormalities and any active medical conditions, as identified by a detailed medical history, complete physical examination, vital signs, clinical laboratory tests, cardiac and ophthalmologic evaluation as assessed by the Investigator.
- Male and female between ≥ 18 and ≤ 65 years of age (at the day of signature of consent).
- Female participants had to be postmenopausal or sterilized. Note: due to preclinical data of teratogenicity and lack of data on human pregnancies with binimetinib, women of childbearing potential were excluded from this study.
Women were considered postmenopausal and not of childbearing potential if they had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/mL and estradiol 220 msec, QRS complex > 110 msec, QT interval corrected using Fridericia's method (QTcF) > 450 msec (male) and > 470 msec (female) ii. Any ST/T wave abnormalities iii. Any atrial or ventricular arrhythmias, which were of clinical significance and could have had an impact on the safety of the participant or the study as determined by the Investigator iv. Any cardiac conduction abnormalities
- 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 might jeopardize the participant in case of participation in the study
Note: The Investigator was to be guided by evidence of any of the following:
- History of inflammatory bowel syndrome, gastritis, ulcers, gastrointestinal or rectal bleeding
- History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, cholecystectomy or bowel resection
- History of, or clinical evidence of, pancreatic injury or pancreatitis
- Clinical evidence of liver disease or liver injury as indicated by abnormal liver function tests such as ALT, AST, GGT, ALP, or serum bilirubin
- Malabsorption syndrome
- History of impaired renal function or elevated creatinine values indicating impaired renal function
- Evidence of urinary tract obstruction or difficulty in voiding at screening
- History of autonomic dysfunction or Gilbert syndrome
- History of immunocompromised status, including a positive human immunodeficiency virus (HIV) infection (enzyme-linked immunosorbent assay and western blot) test result
- A positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus antibody (HCV Ab) or positive COVID-19 test result or other clinically relevant viral infections
- Significant illness within the 2 weeks prior to dosing
- History of clinically significant drug allergy
- History of atopic allergy (asthma, urticaria, and eczematous dermatitis)
- Use of any prescription drugs or over-the-counter (OTC) medications (except acetaminophen, i.e., paracetamol) and vitamins, supplements, and herbal remedies within 2 weeks prior to dosing
- Participants taking acetaminophen (i.e., paracetamol) on a daily basis for more than 2 consecutive days within 1 week prior to dosing was not to be enrolled
- 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]
- Subfoveal choroidal thickness outside of 40μm - 475μm range
- Neuromuscular disorders that were associated with elevated creatine kinase (e.g., inflammatory myopathies, muscular dystrophy, amy
Data sourced from ClinicalTrials.gov (NCT05810740). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.