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

Francis J. Giles, Ophelia Q P Yin, William M. Sallas, Philipp D. Le Coutre, Richard C. Woodman, Oliver G. Ottmann, Michele Baccarani, Hagop M. Kantarjian

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40 Scopus citations

Abstract

Purpose: We evaluated the population pharmacokinetics (PK) and exposure-response relationship of nilotinib in patients with imatinib-resistant or -intolerant chronic myeloid leukemia (CML). Methods: 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 (Cmin) 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. Results: Baseline demographics and CML disease phase did not significantly affect nilotinib PK. Patients with a lower Cmin 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 Cmin. A joint effect of prognostic risk score and Cmin on TTP was significant (P < 0.001). Nilotinib C min was also associated with the occurrence of all-grade elevations in total bilirubin (P < 0.001) and lipase (P = 0.002) levels. Conclusions: When tolerability allows, adherence to the nilotinib dose (400 mg twice daily) in order to maintain sufficient Cmin is important in maximizing the efficacy of nilotinib in patients with imatinib-resistant or -intolerant CML.

Original languageEnglish (US)
Pages (from-to)813-823
Number of pages11
JournalEuropean Journal of Clinical Pharmacology
Volume69
Issue number4
DOIs
StatePublished - Apr 1 2013

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Giles, F. J., Yin, O. Q. P., Sallas, W. M., Le Coutre, P. D., Woodman, R. C., Ottmann, O. G., Baccarani, M., & Kantarjian, H. M. (2013). Nilotinib population pharmacokinetics and exposure-response analysis in patients with imatinib-resistant or -intolerant chronic myeloid leukemia. European Journal of Clinical Pharmacology, 69(4), 813-823. https://doi.org/10.1007/s00228-012-1385-4