Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib

This article describes studies that investigated the pharmacokinetics of nilotinib, a highly specific, oral, second-generation BCR-ABL tyrosine kinase inhibitor. After a once-or twice-daily regimen at doses ranging from 50 to 1,200mg/day in 119 patients with chronic myeloid leukemia (CML), the area under the serum concentration-time curve (AUC) and peak serum concentration (C _max) of nilotinib were found to be nearly dose proportional up to a dose of 400mg once daily. Solubility-limited absorption at higher doses was observed, but this was partially overcome by dividing the daily dose into two. For instance, the administration of 400mg nilotinib twice daily resulted in a 35% increase in AUC as compared to a once-daily dose of 800mg. Exploratory pharmacodynamic assessment showed a general trend of greater reduction in white blood cell (WBC) levels with increase in nilotinib concentrations. This finding was consistent with the observation of an 82% reduction in WBC levels in patients after a regimen of 400mg nilotinib twice daily for 15 days. The type and quantity of food intake variably affected nilotinib absorption. When administered after a high-fat meal, the AUC of nilotinib increased by 50% in CML patients (n = 10) and by 82% in healthy volunteers (n = 44).