Pharmacokinetic profile of novel reduced-dose Danziten™ (nilotinib tablets) versus Tasigna® (nilotinib capsules): in vivo bioequivalence and population pharmacokinetic analysis

Abstract

Purpose: To evaluate single dose pharmacokinetics (PK) of novel reduced-dose film coated Danziten™ (nilotinib tablets) using a population PK approach, establish bioequivalence vs. Tasigna® (nilotinib capsules) and investigate food effects on PK of both formulations. Methods: A population PK model evaluating nilotinib capsules (300 or 400 mg) or tablets (142 or 190 mg) was developed using data from 14 single dose studies and > 30,000 plasma samples from healthy men and women. Steady-state nilotinib concentration–time profiles following twice daily dosing with various treatment and food conditions were simulated using a randomly sampled dataset of 50 subjects. Results: PK was characterized by a 2-compartment model with linear elimination and zero-order absorption with lag time. Bioequivalence was met for all steady state exposure metrics for both doses under fasted conditions. A milligram strength for nilotinib tablets ~ 50% lower than that for capsules resulted in bioequivalent nilotinib exposures. Administration with a low-fat meal under modified fasting conditions increased the bioavailability (BA) of 142 mg and 190 mg nilotinib tablets by 26.0% and 29.3%, respectively, vs. fasting; values for 300 mg and 400 mg capsules were 56.8% and 60.7%. Administration with a high-fat meal under modified fasting conditions increased the BA of 142 and 190 mg nilotinib tablets by 48.6% and 52.2%, respectively; values for 300 and 400 mg capsules were 180.6% and 183.3%. Conclusion: Nilotinib tablets 142 and 190 mg provide bioequivalent exposures to 300 mg and 400 mg capsules under fasted conditions and substantially smaller effects of food on exposure.