Novel Nilotinib Tablet Formulation: Pharmacokinetic Characterization and Effects of Food

Introduction: Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor with demonstrated efficacy in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML). Use of the drug is limited by a boxed warning and a specific dosing regimen that increases treatment complexity. The prescribing information for nilotinib capsules states that they should be administered on an empty stomach and with no food consumed for ≥2 hours (h) before and ≥1 h after dosing. A novel reduced-dose tablet formulation of nilotinib has been developed to provide equivalent bioavailability (BA) under fasted conditions and minimize the effect of food on pharmacokinetics (PK).

Objective: To characterize the PK profile of a novel film-coated tablet formulation of nilotinib, assess the effects of food on nilotinib relative BA, and compare its PK profile to that for nilotinib capsules.

Methods: The PK of nilotinib capsules (300 or 400 mg) and/or novel film-coated tablets (142 or 190 mg) were evaluated in 6 open-label, randomized, single-dose, crossover studies that enrolled a total 384 healthy volunteers. Nilotinib tablets were administered under prandial conditions defined as: (1) fasting, (2) high-fat meal: fasting for 10 h overnight and administration of study drug 2 h after the start of a high-fat, high-calorie, non-vegetarian breakfast, and (3) low-fat meal: fasting for 10 h overnight and administration of study drug 2 h after the start of a low-fat, low-calorie breakfast. Comparison of the PK profiles and formal statistical evaluation was conducted for bioequivalence (BE) of the nilotinib tablet to nilotinib capsule for all of these conditions.

Results: In the fasted state, BE was established for a 142 mg dose of nilotinib tablet with the 300 mg dose nilotinib capsule and for the 190 mg dose of nilotinib tablet with 400 mg dose nilotinib capsule. Nilotinib tablets (142 mg and 190 mg dose) administered in both fed conditions resulted in higher maximum plasma concentrations (C_max) and areas under the time vs. plasma concentration curve from administration extrapolated to infinity (AUC_0-inf) than the observed fasted state. For nilotinib tablets, the increases in C_max and AUC_0-inf were 55% and 59%, respectively for the 190 mg dose when delivered with a low-fat meal and 66% and 64% when delivered with a high-fat meal. The respective values for 400 mg nilotinib capsules delivered with a low-fat meal were 122% and 101% and those for administration with a high-fat meal were 275% and 210%.

Conclusions: Reduced-dose nilotinib film-coated tablets (142 and 190 mg) provide exposures comparable to 300 and 400 mg nilotinib capsules in the fasted state. The PK profile for nilotinib film-coated tablets also results in much smaller increases in exposure vs. the capsules when the drug is taken with food.

Mauro:Sun Pharma/SPARC: Research Funding; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Radich:ThermoFisher: Honoraria. Jain:Azurity Pharmaceuticals: Current Employment. Sequeira:Azurity Pharmaceuticals: Current Employment. Douer:Amgen, Servier: Speakers Bureau; Servier, Jazz: Consultancy.