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

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 Cmin 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.

• Authors: 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
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 69 Issue 4 Pg. 813-23 (Apr 2013) ISSN: 1432-1041 [Electronic] Germany
• PMID: 23052406 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• nilotinib

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, blood, pharmacokinetics, therapeutic use)
• Benzamides (administration & dosage, adverse effects, therapeutic use)
• Biological Availability
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Resistance, Neoplasm
• Female
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (blood, drug therapy)
• Male
• Middle Aged
• Models, Biological
• Piperazines (administration & dosage, adverse effects, therapeutic use)
• Pyrimidines (administration & dosage, adverse effects, blood, pharmacokinetics, therapeutic use)
• Young Adult