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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 (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 < 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 C(min) is important in maximizing the efficacy of nilotinib in patients with imatinib-resistant or -intolerant CML.
European Journal of Clinical Pharmacology 10/2012; · 2.85 Impact Factor
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Richard A Larson,
Ophelia Q P Yin,
Andreas Hochhaus,
Giuseppe Saglio,
Richard E Clark,
Hirohisa Nakamae,
Neil J Gallagher,
Eren Demirhan,
Timothy P Hughes,
Hagop M Kantarjian, Philipp D le Coutre
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ABSTRACT: We investigated the population pharmacokinetics and exposure-response relationship of nilotinib in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase.
Nilotinib was given at 300 mg or 400 mg twice daily. Serum concentration data (sparse and full pharmacokinetic profiles) were obtained from 542 patients over 12 months. A population pharmacokinetic analysis was performed using nonlinear mixed-effect modeling. Exposure-response relationships were explored graphically or using logistic regression models.
Nilotinib concentrations were stable over 12 months. Patients in the 400 mg twice-daily arm had an 11.5% higher exposure than did those in the 300 mg twice-daily arm, and the relative bioavailability of nilotinib 400 mg twice daily was 0.84 times that of 300 mg twice daily. Patient demographics did not significantly affect nilotinib pharmacokinetics. The occurrence of all-grade total bilirubin elevation was significantly higher in patients with higher nilotinib exposure, and a positive correlation was also observed between nilotinib exposure and QTcF change on electrocardiograms from baseline. There was no significant relationship between nilotinib exposure and major molecular response at 12 months.
There is a less than proportional dose-exposure relationship between nilotinib 300 mg and 400 mg twice-daily doses. Blood level testing is unlikely to play an important role in the general management of patients with newly diagnosed CML treated with nilotinib.
European Journal of Clinical Pharmacology 12/2011; 68(5):723-33. · 2.85 Impact Factor
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Jorge E Cortes,
Andreas Hochhaus, Philipp D le Coutre,
Gianantonio Rosti,
Javier Pinilla-Ibarz,
Elias Jabbour,
Kathryn Gillis,
Richard C Woodman,
Rick E Blakesley,
Francis J Giles,
Hagop M Kantarjian,
Michele Baccarani
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ABSTRACT: Nilotinib has significant efficacy in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) and in patients with CML-CP or CML in accelerated phase (CML-AP) after imatinib failure. We investigated the occurrence of cross-intolerance to nilotinib in imatinib-intolerant patients with CML. Only 1/75 (1%) patients with nonhematologic imatinib intolerance experienced a similar grade 3/4 adverse event (AE), and 3/75 (4%) experienced a similar persistent grade 2 nonhematologic AE on nilotinib. Only 7/40 (18%) patients with hematologic imatinib intolerance discontinued nilotinib, all because of grade 3/4 thrombocytopenia. Ninety percent of imatinib-intolerant patients with CML-CP who did not have complete hematologic response (CHR) at baseline (n = 52) achieved CHR on nilotinib. Nilotinib induced a major cytogenetic response in 66% and 41% of patients with imatinib-intolerant CML-CP and CML-AP (complete cytogenetic response in 51% and 30%), respectively. Minimal cross-intolerance was confirmed in patients with imatinib-intolerant CML. The favorable tolerability of nilotinib in patients with imatinib intolerance leads to alleviation of AE-related symptoms and significant and durable responses. In addition to its established clinical benefit in patients with newly diagnosed CML and those resistant to imatinib, nilotinib is effective and well-tolerated for long-term use in patients with imatinib intolerance. This study is registered at http://www.clinicaltrials.gov as NCT00471497.
Blood 04/2011; 117(21):5600-6. · 9.90 Impact Factor
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Hagop M Kantarjian,
Francis J Giles,
Kapil N Bhalla,
Javier Pinilla-Ibarz,
Richard A Larson,
Norbert Gattermann,
Oliver G Ottmann,
Andreas Hochhaus,
Jerald P Radich,
Giuseppe Saglio,
Timothy P Hughes,
Giovanni Martinelli,
Dong-Wook Kim,
Yaping Shou,
Neil J Gallagher,
Rick Blakesley,
Michele Baccarani,
Jorge Cortes, Philipp D le Coutre
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ABSTRACT: Nilotinib is a potent selective inhibitor of the BCR-ABL tyrosine kinase approved for use in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), and in CML-CP and CML-accelerated phase after imatinib failure. Nilotinib (400 mg twice daily) was approved on the basis of the initial results of this phase 2 open-label study. The primary study endpoint was the proportion of patients achieving major cytogenetic response (CyR). All patients were followed for ≥ 24 months or discontinued early. Of 321 patients, 124 (39%) continue on nilotinib treatment. Overall, 59% of patients achieved major CyR; this was complete CyR (CCyR) in 44%. Of patients achieving CCyR, 56% achieved major molecular response. CyRs were durable, with 84% of patients who achieved CCyR maintaining response at 24 months. The overall survival at 24 months was 87%. Adverse events were mostly mild to moderate, generally transient, and easily managed. This study indicates that nilotinib is effective, with a manageable safety profile, and can provide favorable long-term benefits for patients with CML-CP after imatinib failure.
Blood 01/2011; 117(4):1141-5. · 9.90 Impact Factor
