Nilotinib population pharmacokinetics and exposure-response analysis in patients with imatinib-resistant or -intolerant chronic myeloid leukemia

作者：Giles Francis J; Yin Ophelia Q P^*; Sallas William M; le Coutre Philipp D; Woodman Richard C; Ottmann Oliver G; Baccarani Michele; Kantarjian Hagop M

来源：European Journal of Clinical Pharmacology, 2013, 69(4): 813-823.

DOI：10.1007/s00228-012-1385-4

• Nilotinib
• Pharmacokinetic
• Chronic myeloid leukemia
• Resistance
• Intolerance
• Imatinib

We evaluated the population pharmacokinetics (PK) and exposure-response relationship of nilotinib in patients with imatinib-resistant or -intolerant chronic myeloid leukemia (CML). %26lt;br%26gt;Concentration data from 493 patients with CML in chronic phase (CML-CP), accelerated phase, or blast crisis were used to perform a population pharmacokinetic analysis using nonlinear mixed-effect modeling. Steady-state nilotinib trough concentrations (C-min) in individual patients were estimated from the population PK model for correlation with the efficacy and safety variables. Exposure-efficacy analysis was performed in patients with CML-CP, whereas exposure-safety analysis was performed in all patients who had both nilotinib PK data and efficacy/safety measures available. %26lt;br%26gt;Baseline demographics and CML disease phase did not significantly affect nilotinib PK. Patients with a lower C-min had significantly longer time to complete cytogenetic response (P = 0.010), longer time to major molecular response (P = 0.012), shorter time to progression (TTP; P = 0.009), and a trend toward lower response rates vs. patients with higher C-min. A joint effect of prognostic risk score and C-min on TTP was significant (P %26lt; 0.001). Nilotinib C-min was also associated with the occurrence of all-grade elevations in total bilirubin (P %26lt; 0.001) and lipase (P = 0.002) levels. %26lt;br%26gt;When tolerability allows, adherence to the nilotinib dose (400 mg twice daily) in order to maintain sufficient C-min is important in maximizing the efficacy of nilotinib in patients with imatinib-resistant or -intolerant CML.

• 出版日期2013-4