Pharmacokinetic investigation aimed to demonstrate that the new liquid formulation containing (fos)netupitant and palonosetron is similar to the lyophilized (freeze-dried) formulation

INTERVENTION: The study is divided into two parts (A and B). Part A is composed of 3 consecutive cohorts of 8 subjects each (fosnetupitant/palonosetron 235 mg/0.25 mg injectable solution, IV NEPA FDCliq, given over 15, 5, or 2 minutes). Then Part B included 40 subjects randomized in 2 arms (fosnetupitant/palonosetron 235 mg/0.25 mg lyophilized powder (Akynzeo®), IV NEPA FDClyo, diluted in 50 ml given in 30 min vs Liquid given in either 15 or 5 or 2 minutes as resulting from part A) with a cross‐over design. Part A is not randomized, the first 8 subjects are assigned to the first cohort. Part B is randomized 1:1, using a sealed envelope established on a pre‐defined randomization list. Part A: 3 consecutive cohorts of 8 subjects will receive a single IV dose of 20 ml of the liquid formulation corresponding to the fixed‐dose combination fosnetupitant/palonosetron 235 mg/0.25 mg. In each cohort, the injection duration should vary as follows: 1. Cohort 1: 15 min 2. Cohort 2: 5 min 3. Cohort 3: either 2 or 10 min according to the outcome of Cohort 2 Predefined stopping rules will be considered for deciding about continuing with the next cohort and shorter injection duration. After cohort 1, if the injection duration of 15 min is found to be safe and well‐tolerated, 5 min should be tested in cohort 2. After cohort 2, if the injection duration of 5 min is found to be safe and well‐tolerated, 2 min should be tested in cohort 3. Otherwise, 10 min should be investigated. Vital signs and ECGs will be measured pre‐dose, and at 30 min, and 6 h after the injection The PK samples will be collected immediately post‐dose, between (2‐5 or 10‐15 min, on the CONDITION: Breast cancer ; Cancer ; Breast cancer PRIMARY OUTCOME: ; Part A:; 1. The shortest safe and tolerable duration of IV bolus injection of the liquid formulation assessed using the following:; 1.1. Heart rate, electrical axes, and RR, PR, QRS, QT, QTcB, and QTcF intervals measured using electrocardiogram (ECG) at pre‐dose, 30 min, and 6 h post‐dose; 1.2. Systolic blood pressure, diastolic blood pressure, and pulse rate measured using sphygmomanometer at pre‐dose, 30 min, and 6 h post‐dose; 1.3. Adverse events measured from participant history up to 6 days post‐dose; ; Part B:; 1. Bioequivalence of the liquid formulation (at the injection duration defined in Part A) and the lyophilized formulation, estimated in terms of the extent of exposure to netupitant and palonosetron (area under the plasma drug concentration–time curve, AUC0‐t), using a fully validated liquid chromatography with tandem mass spectrometry (LC‐MSMS) at pre‐dose, 30 and 45 min post‐dose, and at 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168 and 192 h post‐dose; SECONDARY OUTCOME: ; Part A:; 1. Characterization of the pharmacokinetic (PK) profile in plasma of fosnetupitant, netupitant, and palonosetron using serum samples after injection of the liquid formulation measured immediately post‐dose, between either 2‐5 or 10‐15 min (on the basis of the treatment period), 20, 30, and 45 min, 1, 1.5, 2, 3, 4, 8, 12 and 24 h post‐dose; ; Part B:; 1. Pharmacokinetic (PK) profile and kinetic parameters of netupitant and palonostren measured using fully validated liquid chromatography with tandem mass spectrometry (LC‐MS‐MS) at pre‐dose, 30 and 45 min post‐dose, and at 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168 and 192 h post‐dose; 2. Safety and tolerability of the liquid formulation and the lyophilized formulation during the overall trial assessed using the following:; 1.1. Heart rate, electrical axes, and RR, PR, QRS, QT, QTcB, and QTcF intervals measured using electrocardiogram (ECG) at pre‐dose, immediately post‐dose, 30 min, 6, and 24 h post‐dose; 1.2. Systolic blood pressure, diastolic blood pressure, and pulse rate measured using sphygmomanometer at pre‐dose, immediately post‐dose, 30 min, 6, and 24 h post‐dose; 1.3. Adverse events measured from participant history up to 9 days post‐dose; INCLUSION CRITERIA: 1. Signed written informed consent before inclusion in the study 2. Aged 18 and 55 years 3. Body Mass Index (BMI) between 18.5 and 30 kg/m2 4. Vital signs, measured after 5 min at rest in the sitting position: 4.1. Systolic blood pressure between 100 and 139 mmHg 4.2. Diastolic blood pressure between 50 and 89 mmHg 4.3. Pulse rate between 50 and 90 bpm 5. Able to comprehend the full nature and purpose of the study, including possible risks and side effects, and able to co‐operate with the Investigator and to comply with the requirements of the entire study 6. Women of child‐bearing potential must have a negative pregnancy test result at screening and admission (Day ‐1) and be using at least one of the following reliable methods of contraception: 6.1. Hormonal oral, implantable,