Imatinib plasma trough levels in chronic myeloid leukaemia: results of a multicentre study CSTI571AIL11TGLIVEC

Abstract

Imatinib has been accepted as frontline treatment for patients with chronic myeloid leukaemia (CML), and patients generally receive doses ranging from 400 to 800 mg/day. Previous studies have demonstrated that maintaining imatinib plasma levels (IMPLs) >1000 ng/mL leads to improved responses and long-term outcomes. However, IMPLs vary among patients because of factors such as drug-drug interactions, adherence, toxicity and differential levels of expression of cellular efflux/influx proteins. In this study, IMPLs were analysed in 191 patients with CML and were compared with achievement of molecular and cytogenetic responses (CyR). IMPLs were also correlated with renal and hepatic dysfunction. Additionally, self-reported adherence was monitored. The median and mean IMPLs were 994 ng/mL and 1070 ± 686 ng/mL, respectively, with 96 patients (50%) achieving plasma levels >1000 ng/mL. Self-reported patient compliance was 98%. Patients who achieved a complete CyR (CCyR) had significantly higher IMPLs (1078 ± 545 ng/mL) than those without CyR (827 ± 323 ng/mL, p = 0.045). When grouped together, patients who achieved a CCyR or partial CyR had significantly higher IMPLs than patients who achieved a minimal CyR or did not achieve a CyR (1066 ng/mL vs 814 ng/mL, p = 0.002). There was no significant difference observed in the IMPLs between patients who achieved molecular responses (n = 177) on treatment (major molecular response, 976 ± 385 ng/mL versus complete molecular response, 1138 ± 809 ng/mL, p = 0.387). Mean IMPLs were similar in patients with or without renal or hepatic impairment. Overall, this study confirmed previous reports that higher IMPLs correlate with clinical responses and demonstrated that imatinib exposure did not differ in patients with or without liver and/or renal dysfunction. The use of IMPL testing and patient diaries may be practical tools for the management of imatinib therapy in patients with CML.

Measurement of adherence to BCR-ABL inhibitor therapy in chronic myeloid leukemia: current situation and future challenges

“…[47][48][49] More recently, studies have indicated that higher imatinib plasma levels correlate with clinical responses and compliance, and also suggest that plasma levels are a means to assess drug toxicity and management of imatinib therapy in patients with CML. 61,62 Of interest, recently a self-assessment questionnaire received preliminary validation in patients with CML receiving imatinib treatment, allowing health care professionals to assess patient adherence during their routine clinical practice. 63 A study using MEMS ® over a 1-year period reported that adherence correlates to drug concentrations in plasma, thus indicating the successful use of electronically monitored dosing histories for modeling pharmacokinetic data.…”

“…In support of the use of such markers, imatinib plasma levels may predict adherence and clinical response, and hence serve as a guide to optimizing therapy in CML patients. [47][48][49] More recently, studies have indicated that higher imatinib plasma levels correlate with clinical responses and compliance, and also suggest that plasma levels are a means to assess drug toxicity and management of imatinib therapy in patients with CML. 61,62 Of interest, recently a self-assessment questionnaire received preliminary validation in patients with CML receiving imatinib treatment, allowing health care professionals to assess patient adherence during their routine clinical practice.…”

Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib for Patients with Chronic Myeloid Leukemia

“…[21][22][23][24][25] Several studies have investigated whether the imatinib C 0 reflects the clinical response of patients taking imatinib, namely exposure-response relationships. 11,12,[20][21][22][25][26][27][28][29][30] In Japanese CML patients, we have reported that the imatinib C 0 was significantly higher in patients with a MMR than in those without a MMR; the mean values were 1107±594 ng/ mL and 873±529 ng/mL, respectively (p=0.002). 21) Picard et al first reported that a steady-state imatinib C 0 measured after at least 12 months of treatment with a standard imatinib dose correlated with the MMR, and the threshold for the imae-mail: m-miura@hos.akita-u.ac.jp tinib C 0 should be set above 1002 ng/mL.…”

“…36) Furthermore, it has also been reported that there was no significant difference in the imatinib C 0 between patients who achieved a MMR (976±385 ng/mL) and a CMR (1138±809 ng/mL). 30) For CMR achievement, a higher imatinib C 0 was not necessary; however, the target imatinib C 0 should still be set above 1000 ng/mL. BCRP, encoded by the ABCG2 gene, is a membrane efflux transporter normally expressed in the small intestine and biliary canalicular front of hepatocytes, 37,38) which is involved in the absorption, distribution, and excretion of a wide variety of clinically relevant drugs.…”

Imatinib and Norimatinib Plasma Levels Analyses of Chronic Myeloid Leukemia Patients

“…Many studies have been conducted to understand the relation of imatinib plasma concentrations with clinical response. [1][2][3] Imatinib is a targeted, potent and competitive TKI; it is designed to selectively interfere with key signal transduction pathways. [4][5][6] It performs its therapeutic activity on CML by competitive inhibition at the ATP-binding site.…”