Cancer Chemother Pharmacol DOI 10.1007/s00280-014-2473-1
Original Article
Population pharmacokinetics of imatinib in Iranian patients with chronic‑phase chronic myeloid leukemia Ali‑Akbar Golabchifar · Saeed Rezaee · Ardeshir Ghavamzadeh · Kamran Alimoghaddam · Nahid Mobarghei Dinan · Mohammad‑Reza Rouini
Received: 9 November 2013 / Accepted: 23 April 2014 © Springer-Verlag Berlin Heidelberg 2014
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
A.-A. Golabchifar · N. M. Dinan · M.-R. Rouini (*) Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, 14155‑651 Tehran, Iran e-mail: [email protected] S. Rezaee Department of Pharmaceutics, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran A. Ghavamzadeh · K. Alimoghaddam Hematology–Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
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)
32.0 [17–67] 35.5 ± 11.9 165 [150–187] 167 ± 9 68.5 [47.0–105.0] 70.8 ± 13.5 24.8 [17.3–43.7] 25.4 ± 4.6 4 11 27 14 1 3 1 38 106 31 8 21
QD (one a day); BID (twice a day); TID (three times a day); QID (four times a day) MMR major molecular response, CCyR complete cytogenetic response
intervals at routine checkups and predefined time intervals. A total of 61 subjects participated in the pharmacokinetic evaluation in two separate occasions, but twenty-two of the 61 subjects participated in three different occasions. Complete medical histories were recorded, and physical examination and laboratory tests including a complete blood count with differential, serum creatinine, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, prothrombin and activated partial thromboplastin time were done at each scheduled visit. The patient characteristics are summarized in Table 1. Blood sampling A sparse sampling method was used for PK study. Pharmacometrician who performed the analysis for this study had no
Cancer Chemother Pharmacol
direct contact with patients. Samples for PK analysis were collected at pre-dose (for estimation of trough level), and at 0.5–6 h post-dose administration in the presence of the nurses. Since the study was done in a population of outpatients taking imatinib for CML, blood samples were not always drawn at the end of the dosage interval; therefore, for correlation analysis, the trough concentrations were estimated using a population PK model allowing sparse and flexible sampling. Patients also did not have the same number and same time of pre- or post-dose samples and varied from one to another occasion. PK blood samples (5 mL each) were collected into EDTA Vacutainer® tubes, centrifuged at 1,500g for 15 min at 4 °C, and separated plasma samples were stored at –70 °C for subsequent analysis. Data from patients for PK analysis, providing a total of 533 plasma samples (after exclusion of 21 samples), were collected over 2 years, and the average, minimum and maximum numbers of measurements in each occasion for patients were 3.70, 2 and 6, respectively. Twenty-one concentrations were unexpected values, probably due to poor patient compliance (observed concentrations
Original Article
Population pharmacokinetics of imatinib in Iranian patients with chronic‑phase chronic myeloid leukemia Ali‑Akbar Golabchifar · Saeed Rezaee · Ardeshir Ghavamzadeh · Kamran Alimoghaddam · Nahid Mobarghei Dinan · Mohammad‑Reza Rouini
Received: 9 November 2013 / Accepted: 23 April 2014 © Springer-Verlag Berlin Heidelberg 2014
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
A.-A. Golabchifar · N. M. Dinan · M.-R. Rouini (*) Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, 14155‑651 Tehran, Iran e-mail: [email protected] S. Rezaee Department of Pharmaceutics, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran A. Ghavamzadeh · K. Alimoghaddam Hematology–Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
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)
32.0 [17–67] 35.5 ± 11.9 165 [150–187] 167 ± 9 68.5 [47.0–105.0] 70.8 ± 13.5 24.8 [17.3–43.7] 25.4 ± 4.6 4 11 27 14 1 3 1 38 106 31 8 21
QD (one a day); BID (twice a day); TID (three times a day); QID (four times a day) MMR major molecular response, CCyR complete cytogenetic response
intervals at routine checkups and predefined time intervals. A total of 61 subjects participated in the pharmacokinetic evaluation in two separate occasions, but twenty-two of the 61 subjects participated in three different occasions. Complete medical histories were recorded, and physical examination and laboratory tests including a complete blood count with differential, serum creatinine, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, prothrombin and activated partial thromboplastin time were done at each scheduled visit. The patient characteristics are summarized in Table 1. Blood sampling A sparse sampling method was used for PK study. Pharmacometrician who performed the analysis for this study had no
Cancer Chemother Pharmacol
direct contact with patients. Samples for PK analysis were collected at pre-dose (for estimation of trough level), and at 0.5–6 h post-dose administration in the presence of the nurses. Since the study was done in a population of outpatients taking imatinib for CML, blood samples were not always drawn at the end of the dosage interval; therefore, for correlation analysis, the trough concentrations were estimated using a population PK model allowing sparse and flexible sampling. Patients also did not have the same number and same time of pre- or post-dose samples and varied from one to another occasion. PK blood samples (5 mL each) were collected into EDTA Vacutainer® tubes, centrifuged at 1,500g for 15 min at 4 °C, and separated plasma samples were stored at –70 °C for subsequent analysis. Data from patients for PK analysis, providing a total of 533 plasma samples (after exclusion of 21 samples), were collected over 2 years, and the average, minimum and maximum numbers of measurements in each occasion for patients were 3.70, 2 and 6, respectively. Twenty-one concentrations were unexpected values, probably due to poor patient compliance (observed concentrations
