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Population pharmacokinetics of imatinib in Iranian patients with chronic-phase chronic myeloid leukemia

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Abstract

Purpose

We evaluated the population pharmacokinetics (PPK) and exposure–response relationship of imatinib mesylate in Iranian patients with chronic myeloid leukemia (CML).This study was designed to assess steady state (SS) imatinib trough concentrations (Cmin) and pharmacokinetics parameters of imatinib in patients with CML in chronic phase after at least 12-month treatment.

Methods

Plasma concentrations from a randomized controlled trial consist of 61 patients who received oral imatinib at doses ranged between 300 and 800 mg in various dosing interval, which were quantified using a validated reversed-phase high-performance liquid chromatographic method with UV detection method on different occasions at SS and evaluated using PPK model.

Results

A one-compartment model with zero-order absorption and a lag time was sufficient in describing the concentration–time profile. Inter-individual variability (IIV) was modeled for all parameters. Oral clearance (CL/F) and the volume of distribution (V/F) were estimated to 10.8 L/h with 30 % IIV and 265 L with 53 % IIV, respectively. Inter-occasion variability (IOV) was included in CL/F (17 %) and V/F (22 %).The proportional residual error of the model was 8 %.

Conclusions

Simulation analysis from individual parameters shows exposure to imatinib is highly variable among patients. Imatinib trough plasma levels <1,257 ng/mL were associated with lower rates of major molecular response. Because of the wide IIV compared with IOV with imatinib in our study, trough levels may play a role in investigating instances of suboptimal response.

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Acknowledgments

This study was part of a PhD thesis supported by Tehran University of Medical Sciences (TUMS).

Conflict of interest

None.

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Authors and Affiliations

  1. Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, 14155-651, Tehran, Iran

    Ali-Akbar Golabchifar, Nahid Mobarghei Dinan & Mohammad-Reza Rouini

  2. Department of Pharmaceutics, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran

    Saeed Rezaee

  3. Hematology–Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Ardeshir Ghavamzadeh & Kamran Alimoghaddam

Authors
  1. Ali-Akbar Golabchifar
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  2. Saeed Rezaee
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  3. Ardeshir Ghavamzadeh
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  4. Kamran Alimoghaddam
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  5. Nahid Mobarghei Dinan
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  6. Mohammad-Reza Rouini
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Correspondence to Mohammad-Reza Rouini.

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Golabchifar, AA., Rezaee, S., Ghavamzadeh, A. et al. Population pharmacokinetics of imatinib in Iranian patients with chronic-phase chronic myeloid leukemia. Cancer Chemother Pharmacol 74, 85–93 (2014). https://doi.org/10.1007/s00280-014-2473-1

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  • DOI: https://doi.org/10.1007/s00280-014-2473-1

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