ABSTRACT
Title
Therapeutic drug monitoring of imatinib in patients affected by chronic myeloid leukemia
Authors
M. Lastella1, S. Galimberti2, M. Polillo1, M. Rousseau2, E. Sordi2, C. Baratè2, M. Petrini2, R. Danesi1, A. Di Paolo1
1 Div. of Pharmacology, Dept. of Internal Medicine, University of Pisa
2 Div. of Hematology, Dept. of Oncology, Transplants and New Technologies in Medicine, University of Pisa
1 Div. of Pharmacology, Dept. of Internal Medicine, University of Pisa
2 Div. of Hematology, Dept. of Oncology, Transplants and New Technologies in Medicine, University of Pisa
Abstract
Background. In Western Countries, the incidence of chronic myeloid leukemia (CML) is 1-2 cases/100 000/year, and median age at diagnosis is approximately 60 years. Leukemia cells are characterized by the presence of the Philadelphia (Ph) chromosome and by the synthesis of the BCR-ABL protein, which is involved in leukemogenesis. The chronic indolent phase of CML may last for 3-4 years until when an accelerated/blastic phase occurrs. Recently, the introduction into clinical practice of drugs able to inhibit the tyrosine-kinase activity of BCR-ABL protein, as well as imatinib, has led to a significant improvement of CML patients’ survival. Major advantages of tyrosine kinase inhibitors (TKis) are represented by high efficacy, oral administration of a standard daily dose and good tolerability. Moreover, the highest therapeutic benefit is expected when minimal plasma concentrations (Cmin) of imatinib are equal or greater than 1000 ng/mL [Picard et al, 2007; Takahashi et al, 2010]. However, imatinib pharmacokinetics is influenced by several physiological (age, body weight, plasma protein concentrations), pathological (liver and kidney function) and pharmacogenetic factors (polymorphisms of transmembrane transporters) [Petain et al, 2008; Yoo et al, 2010], while poor adherence to the schedule should be considered as an additional cause of treatment failure [Marin et al, 2010]. For these reasons, a therapeutic drug monitoring protocol should deserve particular attention in CML patients receiving imatinib.
Aim. The aim of the present study was the application of a therapeutic monitoring protocol for imatinib in CML patients.
Patients and methods. Twenty-one patients, 11 men and 10 women (mean±SD age, 60.6±11.9 and 56.4±14.8 years, respectively) affected by CML and treated with imatinib for at least 14 days were enrolled. Drug daily dose was 400 mg, except for two women (300 mg) and a man (600 mg). At different time points from drug administration, blood samples were obtained, centrifuged and plasma was prepared according to a solid-phase extraction procedure and analysed by a high performance liquid chromatography method with UV detection. The MWPharm software (MediWare, Holland) was used to obtain simulated imatinib plasma profile in every patient on the basis of measured drug plasma concentrations according to a two-compartmental pharmacokinetic model. Age, height, body weight and plasma creatinine, characterized by coefficient of variation (CV) values ranging from 6.4% up to 33.7%, were considered as covariates during pharmacokinetics analysis in order to improve model performance.
Results. Pharmacokinetic analysis revealed a wide interpatient variability for all of the parameters investigated. In particular, clearance (CL/F) and volume of distribution (Vd/F) of imatinib were 14.2±7.1 L/h (CV, 50.2%) and 284±48 L (CV, 17.0%), respectively, while terminal half-life accounted for 16.4±6.7 h (CV, 41.1%), and these results were in agreement with those previously reported [Widmer et al, 2006]. The Vd/F was significantly greater in men (312.5±39.3 L) with respect to that calculated in women (252.5±36.9 L).
Mean maximal plasma concentration of imatinib was 2380±540 ng/mL, while trough concentration accounted for 802±465 ng/mL. It is worth noting that only 6 and 13 patients had Cmin values higher than 1000 and 500 ng/mL, respectively.
Conclusion. The present results confirm that variability in imatinib pharmacokinetics is not negligible among individuals, and the administration of a standard dose may be associated with low, sub-therapeutic plasma concentrations in some patients.
References
Marin et al. J Clin Oncol. 2010; 28: 2381-8
Petain et al. Clin Cancer Res. 2008; 14: 7102-9
Picard et al. Blood. 2007; 109: 3496-9
Takahashi et al. Clin Pharmacol Ther. 2010; 88: 809-13
Widmer et al. Br J Clin Pharmacol. 2006; 62: 97-112
Yoo et al. J Clin Oncol. 2010; 28: 1554-9
Aim. The aim of the present study was the application of a therapeutic monitoring protocol for imatinib in CML patients.
Patients and methods. Twenty-one patients, 11 men and 10 women (mean±SD age, 60.6±11.9 and 56.4±14.8 years, respectively) affected by CML and treated with imatinib for at least 14 days were enrolled. Drug daily dose was 400 mg, except for two women (300 mg) and a man (600 mg). At different time points from drug administration, blood samples were obtained, centrifuged and plasma was prepared according to a solid-phase extraction procedure and analysed by a high performance liquid chromatography method with UV detection. The MWPharm software (MediWare, Holland) was used to obtain simulated imatinib plasma profile in every patient on the basis of measured drug plasma concentrations according to a two-compartmental pharmacokinetic model. Age, height, body weight and plasma creatinine, characterized by coefficient of variation (CV) values ranging from 6.4% up to 33.7%, were considered as covariates during pharmacokinetics analysis in order to improve model performance.
Results. Pharmacokinetic analysis revealed a wide interpatient variability for all of the parameters investigated. In particular, clearance (CL/F) and volume of distribution (Vd/F) of imatinib were 14.2±7.1 L/h (CV, 50.2%) and 284±48 L (CV, 17.0%), respectively, while terminal half-life accounted for 16.4±6.7 h (CV, 41.1%), and these results were in agreement with those previously reported [Widmer et al, 2006]. The Vd/F was significantly greater in men (312.5±39.3 L) with respect to that calculated in women (252.5±36.9 L).
Mean maximal plasma concentration of imatinib was 2380±540 ng/mL, while trough concentration accounted for 802±465 ng/mL. It is worth noting that only 6 and 13 patients had Cmin values higher than 1000 and 500 ng/mL, respectively.
Conclusion. The present results confirm that variability in imatinib pharmacokinetics is not negligible among individuals, and the administration of a standard dose may be associated with low, sub-therapeutic plasma concentrations in some patients.
References
Marin et al. J Clin Oncol. 2010; 28: 2381-8
Petain et al. Clin Cancer Res. 2008; 14: 7102-9
Picard et al. Blood. 2007; 109: 3496-9
Takahashi et al. Clin Pharmacol Ther. 2010; 88: 809-13
Widmer et al. Br J Clin Pharmacol. 2006; 62: 97-112
Yoo et al. J Clin Oncol. 2010; 28: 1554-9