Part A, Dose Calibration Cohort:
This is a crossover design dose calibration study in healthy volunteers to identify a dose of IkT-001Pro film-coated tablets that would be equivalent to imatinib free base 400 mg film-coated tablets containing imatinib mesylate.
Dose calibration cohorts will each consist of eight (8) subjects who will receive a single dose of IkT-001Pro at 400, 500 or 600 mg and then crossover to a single dose of imatinib 400 mg delivered as imatinib mesylate following a 7-day washout. The three cohorts will have staggered starting points. The 400 mg IkT-001Pro dose, washout and 400 mg imatinib delivered as imatinib mesylate will be completed first including full PK analysis. Following review of the PK data at 400 mg IkT-001Pro, the 500 mg and 600 mg cohorts will be enrolled approximately simultaneously.
Pharmacokinetic plasma samples for all three cohorts will be drawn pre-dose at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72 and 96 hours after dosing. A 7-day washout period will take place between dosing of IkT-001Pro and dosing of 400 mg imatinib delivered as imatinib mesylate. PK plasma samples for the imatinib mesylate arm will be obtained on the same sampling schedule as the IkT-001Pro arm.
Part B- Dose Equivalence Cohort:
Part B will test the bioequivalence of the IkT-001Pro dose chosen in Part A. In this two-period crossover design dose equivalence study, up to 16 subjects will receive IkT-001Pro and up to 16 subjects will receive 400 mg imatinib as imatinib mesylate as a single dose. The dose of IkT-001Pro will be computed from the exposures measured in Part A to estimate the dose of IkT-001Pro that should be equivalent to 400 mg imatinib delivered as imatinib mesylate. After a 7-day washout period, the subjects that began on IkT-001Pro will switch to 400 mg imatinib delivered as imatinib mesylate. Similarly, the subjects that began on 400 mg imatinib delivered as imatinib mesylate will switch to the equivalent dose of IkT-001Pro. Blood samples for PK assessment will be drawn pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72 and 96 hours after dosing for both IkT-001Pro and 400 mg imatinib.
Part C- Dose Equivalence at 600 mg:
Part C will test the single dose bioequivalence of imatinib free base delivered as the equivalent dose IkT-001Pro dose computed from Part A to single dose of imatinib delivered as 600 mg imatinib mesylate. Up to eight (8) subjects will be administered a single dose of 800 mg IkT-001Pro. After a 7-day washout period, the subjects will switch to 600 mg imatinib free base delivered as imatinib mesylate.
Blood samples for PK assessment will be drawn pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72 and 96 hrs post-dose on Day 1. The same sampling schedule will be followed for the IkT-001Pro and imatinib mesylate dosing periods.
General Methodological Considerations:
The Dose Calibration and Dose Equivalence cohorts will consist of up to 14 visits over a period of up to 28 days prior to dosing and 28 days after dosing. The dose-escalation pattern and timing for IkT-001Pro in Part A or Part B may be modified by the Safety Review Committee (SRC).
Subjects in each cohort of the study will be admitted to the unit approximately 24 hours prior to the expected time of dosing. They will be confined to the unit for approximately 96 hours in Part A and Part B of the study for each drug product to be administered. Subjects will not be confined to the unit during the wash-out period. No subject may be discharged from the unit until the investigator is satisfied that they have no continuing adverse events that could be related to study drug.
A full breakfast must be given no more than 60 mins prior to dosing in Parts A and B. The meal must be a high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal. The meal should derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively. The caloric breakdown of the meal must be provided in the study report. The single dose of IkT-001Pro or 400 imatinib delivered as imatinib mesylate is to be taken after the meal with a large glass of water (240 ml or 8 oz).
