Population pharmacokinetics of imatinib mesylate in patients with chronic‐phase chronic myeloid leukaemia: results of a phase III study

Schmidli, Heinz; Peng, Bin; Riviere, Gilles-Jacques; Capdeville, Renaud; Hensley, Martee L.; Gathmann, Insa; Bolton, Ann E.; Racine-Poon, Amy

doi:10.1111/j.1365-2125.2005.02372.x

Cited by 107 publications

(87 citation statements)

References 13 publications

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“…1). This model was previously used by Schmidli et al to analyze data from 371 patients (18). Moreover, alternative structural models (i.e., first-order absorption, two-compartment model) were not associated with a lower objective function value.…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Relationships of Imatinib and Its Main Metabolite in Patients with Advanced Gastrointestinal Stromal Tumors

Delbaldo¹,

Chatelut

Ré³

et al. 2006

Clinical Cancer Research

140

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Purpose: This study explored factors affecting the pharmacokinetic variability of imatinib and CGP 74588, and the pharmacokinetic-pharmacodynamic correlations in patients with advanced gastrointestinal stromal tumors. Experimental Design: Thirty-five patients with advanced gastrointestinal stromal tumors received 400 mg of imatinib daily. Six blood samples were drawn: before intake, during 1-to 3-and 6-to 9-hour intervals after intake on day1, and before intake on days 2, 30, and 60. Plasma imatinib and CGP 74588 concentrations were quantified by reverse-phase high-performance liquid chromatography coupled with tandem mass spectrometry, and analyzed by the population pharmacokinetic method (NONMEM program). The influence of 17 covariates on imatinib clearance (CL) and CGP 74588 clearance (CLM/fm) was studied. These covariates included clinical and biological variables and occasion (OCC = 0 for pharmacokinetic data corresponding to the first administration, or OCC = 1for the day 30 or 60 administrations). Results: The best regression formulas were: CL (L/h) = 7.97 (AAG/1.15) À0.52 , and CLM/fm (L/h) = 58.6 (AAG/1.15) À0.60 Â 0.55 OCC , with the plasma a1-acid glycoprotein (AAG) levels indicating that both clearance values decreased at a higher AAG level. A significant timedependent decrease in CLM/fm was evidenced with a mean (+SD) CGP 74588/imatinib area under the curve (AUC) ratio of 0.25 (F0.07) at steady state, compared with 0.14 (F0.03) on day 1. Hematologic toxicity was correlated with pharmacokinetic variables: the correlation observed with the estimated unbound imatinib AUC at steady-state (r = 0.56, P < 0.001) was larger than that of the total imatinib AUC (r = 0.32, NS). Conclusions: The plasma AAG levels influenced imatinib pharmacokinetics. A protein-binding phenomenon needs to be considered when exploring the correlations between pharmacokinetics and pharmacodynamics.

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Section: Resultsmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Relationships of Imatinib and Its Main Metabolite in Patients with Advanced Gastrointestinal Stromal Tumors

Delbaldo¹,

Chatelut

Ré³

et al. 2006

Clinical Cancer Research

140

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“…The pharmacokinetics of imatinib has been extensively studied in Caucasian CML patients [17][18][19][20][21] . However, few studies have been reported on naïve Chinese.…”

Section: Discussionmentioning

confidence: 99%

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

Chen

et al. 2010

Acta Pharmacol Sin

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Aim: To investigate the pharmacokinetics of imatinib in Chinese chronic myelogenous leukemia (CML) patients. Methods: Fourty-six naïve Chinese CML patients treated with imatinib (400 and 600 mg daily, n=36 and 10, respectively) were recruited. The correlations of imatinib (400 mg) trough plasma concentrations (C mins ) with the patients' characteristics and responses were analyzed. Results: The overall mean (±SD, CV%) steady-state C mins for imatinib at 400 mg (n=36) and 600 mg (n=10) daily was 1325.61 ng/mL (±583.53 ng/mL; 44%) and 1550.90 ng/mL (±462.63 ng/mL; 30%), respectively, and no statistically significant differences were found between them (P=0.267). At 400 mg daily, female patients had significantly higher C mins than the male patients (P=0.048), and molecular responses were not correlated with imatinib C mins , but they were correlated with time elapsed before imatinib therapy. Conclusion:The results suggest that Chinese CML patients have higher imatinib C mins than their Caucasian counterparts and that the optimal initial imatinib dose for them requires further investigation.

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“…Likewise, population analysis of imatinib pharmacokinetics showed that ethnic effect was not significant. 17 Since imatinib exhibits dose proportionality from 25 to 1000 mg and it is reported that there is no difference in pharmacokinetics between healthy adults and patients, the results from the present study can be extrapolated to the targeted patients.…”

Section: Resultsmentioning

confidence: 90%

Rapid Determination of Imatinib in Human Plasma by Liquid Chromatography-Tandem Mass Spectrometry: Application to a Pharmacokinetic Study

Yang¹,

Cho²,

Huh³

et al. 2013

Bulletin of the Korean Chemical Society

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A simple, fast and robust analytical method was developed to determine imatinib in human plasma using liquid chromatography-tandem mass spectrometry with electrospray ionization in the positive ion mode. Imatinib and labeled internal standard were extracted from plasma with a simple protein precipitation. The chromatographic separation was performed using an isocratic elution of mobile phase involving 5.0 mM ammonium formate in water-5.0 mM ammonium formate in methanol (30:70, v/v) over 3.0 min on reversed-stationary phase. The detection was performed using a triple-quadrupole tandem mass spectrometer in multiple-reaction monitoring mode. The developed method was validated with lower limit of quantification of 10 ng/mL. The calibration curve was linear over 10-2000 ng/mL (R 2 > 0.99). The method validation parameters met the acceptance criteria. The spiked samples and standard solutions were stable under conditions for storage and handling. The reliable method was successfully applied to real sample analyses and thus a pharmacokinetic study in 27 healthy Korean male volunteers.

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Population pharmacokinetics of imatinib mesylate in patients with chronic‐phase chronic myeloid leukaemia: results of a phase III study

Cited by 107 publications

References 13 publications

Pharmacokinetic-Pharmacodynamic Relationships of Imatinib and Its Main Metabolite in Patients with Advanced Gastrointestinal Stromal Tumors

Pharmacokinetic-Pharmacodynamic Relationships of Imatinib and Its Main Metabolite in Patients with Advanced Gastrointestinal Stromal Tumors

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

Rapid Determination of Imatinib in Human Plasma by Liquid Chromatography-Tandem Mass Spectrometry: Application to a Pharmacokinetic Study

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