CML-362 Study to Evaluate the Effect of Fatty Meals on Nilotinib Drug Levels in Patients of Chronic Myeloid Leukemia–Chronic Phase and Correlate Its In-Vivo Activity With STAT1, STAT5, and AKT 1 Levels

Abstract

Nilotinib is an oral tyrosine kinase inhibitor recommended to be administered in a fasting state (meals taken either 2 hours after or 1 hour before a dose). Fat-rich food has shown to increase the bioavailability of drugs. However, if the drug is allowed to be taken with food, it decreases the dose required to produce the desired clinical efficacy, lowering the cost of treatment and enhancing quality of life. Downstream pathway assessment will be helpful in evaluating the pharmacodynamics of the drug. To assess the effect of fatty meals on nilotinib drug levels and correlate its in-vivo activity with STAT1, STAT5, and AKT1 levels. Design/Setting/Patients/Intervention: This single-center, open-label, pharmacokinetic /pharmacodynamic study included 30 patients with newly diagnosed CML-chronic phase. There were 5 cohorts with 6 patients enrolled in each. The dose of nilotinib in each cohort was 150 mg OD, 200 mg OD, 150 mg BD, 200 mg BD, and 300 mg BD. The drug was given on an empty stomach for the initial 8 days and with fatty meals for the next 8 days. Fatty meals were defined as 2 slices of bread with 10 g butter. Blood (2 mL) was withdrawn at specified time points: 0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 hours on day 1 and 0 and 3 hours on day 8. Nilotinib drug levels were estimated by liquid chromatography mass spectrometry. For assessment of the downstream signaling pathway, blood samples were drawn on days 1 and 8 of drug intake without food and day 8 of drug intake with food, and levels were assessed by ELISA. To assess serum drug levels of nilotinib along with STAT5, STAT1, and AKT1 levels in fasting and post-meal status. Nilotinib had a significant dose-dependent food interaction, and higher doses showed greater increases in AUC and Cmax. The protein expression of the native form of STAT1 increased in the group of drug intake with food. The increase might have resulted from inhibition of STAT1 phosphorylation by nilotinib. The study is funded by a research grant from ICMR, New Delhi.