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

• Published in: European journal of clinical pharmacology 2013-04, Vol.69 (4), p.813-823
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Benzamides - administration & dosage; Benzamides - adverse effects; Benzamides - therapeutic use; Biological and medical sciences; Biological Availability; Biomedical and Life Sciences; Biomedicine; Chronic illnesses; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug resistance; Drug Resistance, Neoplasm; Drug therapy; Female; Hematologic and hematopoietic diseases; Humans; Imatinib Mesylate; Kinetics; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - blood; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Models, Biological; Pharmacokinetics and Disposition; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Piperazines - administration & dosage; Piperazines - adverse effects; Piperazines - therapeutic use; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Pyrimidines - therapeutic use; Young Adult
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-012-1385-4

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 (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. Results 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