Imatinib Plasma Trough Levels Research Articles

CO-RELATION OF P-GLYCOPROTEIN AND PLASMA IMATINIB IN IMATINIB RESPONDERS AND NON-RESPONDERS PATIENTS WITH CHRONIC MYELOID LEUKAEMIA

Objective: To measure and compare P-glycoprotein (P-gp) expressions in imatinib responders and non-responders with chronic myeloid leukemia-chronic phase (CML-CP) and correlate with plasma imatinib levels. Methods: Patients were classified into two groups based on their haematological and cytogenetic responses to imatinib: responders and non-responders. Liquid chromatography-mass spectrometry was used to measure plasma imatinib levels, while flow cytometry was used to evaluate leucocyte P-gp expression. Results: The median plasma imatinib trough levels in non-responders were 496 (217-3150) ng/ml compared to 2245 (454-4270) ng/ml in the responders, which was statistically significant (p=0.0003). The proportion of patients expressing P-gp in granulocytes was higher in the non-responder group than in the responder group (75% vs. 62.5%). The ratio of mean fluorescence intensity (RFI) revealed that non-responders had higher median P-gp expression than did respondents MFI (1.16(1.06-1.50) and 1.12(1.01-1.38), respectively; p = 0. 2307). In both groups, there was a negative correlation between P-gp expression and plasma imatinib trough levels (-0.4384 vs.-0.2848). Conclusion: Imatinib median plasma trough levels in non-responders were considerably lower. This was highly supported by P-gp expression in granulocytes, which is inversely related to imatinib plasma trough levels; however, the difference was not statistically significant, which could be attributed to the small number of patients. This could be the cause of imatinib resistance in non-responder CML-CP patients, and P-gp levels should be evaluated to optimize treatment in patients who do not achieve hematologic or cytogenetic response.

Changes in imatinib plasma trough level during long-term treatment in patients with intermediate- or high-risk gastrointestinal stromal tumors: Relationship between covariates and imatinib plasma trough level.

Imatinib is the first-line adjuvant treatment for gastrointestinal stromal tumors (GISTs). Considering that some studies have suggested that imatinib (IM) plasma trough levels (Cmin) change with time, the aim of this study is to assess the changes in IM Cmin in patients with GIST in a long-term study and to elucidate the relationships between clinicopathological features and IM Cmin. In 204 patients with intermediate- or high-risk GIST who were taking IM, IM Cmin was analyzed. Patient data were grouped according to the duration of medication (A: 1-3 months, B: 4-6 months, C: 7-9 months, D: 10-12 months, E: ≤12 months, F: 12<-≤36 months, G: >36 months). The correlation between IM Cmin at different time stages and clinicopathological characteristics was assessed. Statistically significant differences were observed between Groups A, C, and D (P = 0.049 and 0.01, respectively). In Group E, IM Cmin correlated with sex (P = 0.049) and age (P = 0.029) and negatively correlated with body weight, height, and body surface area (P = 0.007, 0.002, and 0.001, respectively). In Groups F and G, IM Cmin was significantly higher in non-gastric operation patients than in patients with gastrectomy (P = 0.002, 0.036) and was significantly higher in patients with the primary sites of others than in the stomach (P < 0.001, = 0.012). In addition, IM Cmin was much higher in patients with mutation sites other than KIT exon 11 in Group F (P = 0.011). This is the first study of IM Cmin during the long-term treatment of patients with intermediate- or high-risk GIST. IM Cmin was the highest for the first 3 months and then declined, and long-term administration of IM showed a relatively stable plasma trough level. The IM Cmin correlated with different clinical characteristics at different durations of medication. This meant that future "trough level-clinicopathological characteristics" analyses should be time-point-specific. We also need to formulate time-specific medication monitoring plans in clinical practice to study disease progression caused by the occurrence of drug resistance.

Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis.

Adequate imatinib plasma levels are necessary to guarantee an efficacious and safe treatment in gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia (CML) patients. Imatinib is a substrate of the drug transporters ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) that can affect its plasma concentration. In the present study, the association between three genetic polymorphisms in ABCB1 (rs1045642, rs2032582, rs1128503) and one in ABCG2 (rs2231142) and the imatinib plasma trough concentration (Ctrough) was investigated in 33 GIST patients enrolled in a prospective clinical trial. The results of the study were meta-analyzed with those of other seven studies (including a total of 649 patients) selected from the literature through a systematic review process. The ABCG2 c.421C>A genotype demonstrated, in our cohort of patients, a borderline association with imatinib plasma trough levels that became significant in the meta-analysis. Specifically, homozygous carriers of the ABCG2 c.421 A allele showed higher imatinib plasma Ctrough with respect to the CC/CA carriers (Ctrough, 1463.2 ng/mL AA, vs. 1196.6 ng/mL CC + AC, p = 0.04) in 293 patients eligible for the evaluation of this polymorphism in the meta-analysis. The results remained significant under the additive model. No significant association could be described between ABCB1 polymorphisms and imatinib Ctrough, neither in our cohort nor in the meta-analysis. In conclusion, our results and the available literature studies sustain an association between ABCG2 c.421C>A and imatinib plasma Ctrough in GIST and CML patients.

Relative Factors Analysis of Imatinib Trough Concentration in Chinese Patients with Gastrointestinal Stromal Tumor

Aims: Imatinib plasma trough levels (IM C_min) have been reported to have a considerable clinical impact in patients with gastrointestinal stromal tumors (GISTs). We therefore have investigated the factors affecting IM plasma concentration in Chinese GIST patients. Methods: IM C_min in 190 patients with GIST who were taking IM were measured. Results: In patients treated with IM 300 mg/day (n = 16), 400 mg/day (n = 168), and > 400 mg/day (500: n = 1, 600: n = 5), IM C_min was 1,564.54 ± 596.15, 1,521.26 ± 610.33, and 2,540.31 ± 1,298.14 ng/mL, respectively. Of the 168 patients treated with IM 400 mg/day, IM C_min was significantly lower in males (1,353.94 ± 492.89 ng/mL) than in females (1,680.79 ± 669.03 ng/mL, p < 0.01), and in patients with gastrectomy (1,439.60 ± 587.66 ng/mL) than those without gastrectomy (1,649.88 ± 620.12 ng/mL) (p = 0.033). High IM C_min was correlated with low body weight (p = 0.004) and low body surface area (p < 0.001). Conclusion: IM C_min at steady state was significantly associated with body weight and body surface area. Monitoring of IM C_min might be particularly important for the optimal treatment with IM of male patients and those who have undergone gastrectomy.

The clinical relevance of imatinib plasma trough concentrations in chronic myeloid leukemia. A Belgian study

This retrospective multicenter study in patients with chronic myeloid leukemia in chronic phase was undertaken to confirm the clinical relevance of imatinib plasma concentrations monitoring in daily practice. Forty-one patients, with 47 imatinib plasma measurements, were analyzed during treatment with imatinib given at a fixed 400mg daily dose. A significant inverse relationship of imatinib concentration with the patients' weight was observed (Pearson's test: p=0.02, R2=0.1). More interestingly, patients with poor response (switched to another tyrosine kinase inhibitor because of imatinib failure, or because of disease progression after an initial response) displayed a significantly lower mean imatinib concentration as compared to patients maintained on imatinib (822ng/mL vs 1099ng/mL; Student's t-test, p=0.04). Failure or disease progression occurred more often in patients in the lowest quartile of imatinib concentrations compared to patients in the highest quartile (p=0.02, logrank test). No correlation could be established with other biological or clinical parameter, including complete cytogenic response and major molecular response. In conclusion: in patients treated with imatinib at a fixed daily dose of 400mg, imatinib plasma concentrations decreased with increasing body weight and were lower in patients switched to another tyrosine kinase inhibitor due to imatinib failure. Systematic determination of imatinib plasma trough levels should be encouraged in such patients.

TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets

AbstractThe Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study enrolled 210 patients with chronic phase chronic myeloid leukemia (CML) in two equal, sequential cohorts. All started treatment with imatinib 600 mg/day. Imatinib plasma trough level was performed at day 22 and if <1000 ng/mL, imatinib 800 mg/day was given. Patients were then assessed against molecular targets: BCR-ABL1 ≤10’, ≤1’, and ≤0.1’ at 3, 6, and 12 months, respectively. Cohort 1 patients failing any target escalated to imatinib 800 mg/day, and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later. Cohort 2 patients failing any target switched to nilotinib directly, as did patients with intolerance or loss of response in either cohort. At 2 years, 55’ of patients remained on imatinib, and 30’ on nilotinib. Only 12’ were >10’ BCR-ABL1 at 3 months. Confirmed major molecular response was achieved in 64’ at 12 months and 73’ at 24 months. MR4.5 (BCR-ABL1 ≤0.0032’) at 24 months was 34’. Overall survival was 96’ and transformation-free survival was 95’ at 3 years. This trial supports the feasibility and efficacy of an imatinib-based approach with selective, early switching to nilotinib. This trial was registered at www.anzctr.org.au as ’12607000325404.

Association of ABCG2 polymorphism with clinical efficacy of imatinib in patients with gastrointestinal stromal tumor.

Imatinib is a substrate of drug transporters and metabolizing enzymes, including members of the cytochrome P450 (CYP) system. Differences in imatinib pharmacokinetics among individuals might be influenced by genetic polymorphisms and be associated with variable clinical imatinib efficacy. This study sought to test how genetic polymorphisms can affect the clinical efficacy of imatinib and its blood levels in GIST patients. A total of 209 GIST patients who had received imatinib 400 mg daily were genotyped for six single-nucleotide polymorphisms in three genes (CYP3A5 6986A>G; ABCB1 1236C>T, 2677G>A/T, and 3435C>T; and ABCG2 34G>A and 421C>A) via blood samples. Progression-free survival (PFS) and imatinib plasma trough levels were evaluated and compared according to genotypes. With a median follow-up of 39.6 months (range 16.7-97.5 months), the estimated 5-year PFS rate was 67.5 % (95 % CI 59.9-75.1). Among the CYP3A5, ABCB1, and ABCG2 genotypes, ABCG2 421C>A was associated with PFS. The 5-year PFS rate in patients with the AA variant of ABCG2 421C>A (92.3 %; 95 % CI 77.8-100.0) was significantly superior to that of patients with CC/CA genotypes (65.0 %; 95 % CI 56.9-73.1; p = 0.047). For the imatinib trough levels, there were no statistically significant differences when comparing polymorphisms among all genotypes, even after adjusting for clinical factors, including sex, age, body surface area, hemoglobin, albumin, and creatinine clearance. The ABCG2 421C>A genetic variation could influence clinical efficacy in terms of PFS in patients with advanced GIST undergoing imatinib therapy.

Efficacy, safety, and pharmacokinetics of imatinib dose escalation to 800 mg/day in patients with advanced gastrointestinal stromal tumors

Imatinib dose escalation has been suggested as an effective therapy for advanced gastrointestinal stromal tumors (GIST) after progression on the standard dose. We evaluated the efficacy, tolerability, and pharmacokinetics of imatinib dose escalation. Eighty-four patients with GIST who received imatinib 800 mg/day as second-line therapy were reviewed. In 66 patients, imatinib plasma trough level (Cmin) at 800 mg/day was measured. The relationships between imatinib exposure and therapeutic efficacy or toxicity were examined by grouping patients into quartiles according to Cmin and its percent change after dose escalation. Disease control was achieved in 56 % of patients. The median progression-free survival (PFS) was 5.1 months. There was a strong tendency for better PFS in patients with KIT exon 9 mutations compared to patients with other genotypes (median PFS 11 vs 4 months, p=0.051). The common grade 3-4 toxicities were anemia (26 %), neutropenia (11 %), and hemorrhage (5 %). Mean ± standard deviation imatinib Cmin at 800 mg/day and percent Cmin change was 3,552 ± 1,540 ng/mL and 160 ± 101 %, respectively. Body surface area, hemoglobin, and absolute neutrophil count were independent covariates of Cmin at 800 mg/day. Neither Cmin nor its percent change associated with efficacy. The upper three quartiles of percent Cmin change associated with more frequent severe toxicities (56 %) than the lowest quartile (10 %; p=0.01). Dose escalation to 800 mg/day was active and feasible in GIST after progression on the standard dose. Imatinib Cmin monitoring may help to manage the patients with standard dose-resistant GIST that may require dose escalation.

Pharmacokinetics of escalated dose of imatinib in patients with advanced gastrointestinal stromal tumors.

10085 Background: Although escalated dose (ED, 800 mg daily) of imatinib (IM) is one of important options in resistant gastrointestinal stromal tumors (GIST) on standard dose (SD, 400mg daily), there has been lack of pharmacokinetic data at ED. We therefore explore the potential relationship between IM plasma trough level (Cmin), and clinical outcomes or toxicities in patients treated with ED. Methods: Between 2008 and 2011, steady-state IM Cmin was measured in 66 patients with GIST who received ED of IM using liquid chromatography-tandem mass spectrometry. Percent change from IM Cmin at SD was calculated in 43 patients that both SD and ED IM Cmin were measured. The association with efficacy and toxicity was analyzed with grouping patients into quartiles according to IM Cmin at ED and percent change. Results: Median age was 59 years (range, 36–77) and 40 patients were male. KIT exon 11 and 9 mutation was detected in 32 and 18 patients, respectively. At ED, partial response was achieved in 4 patients (6%) and stable disease was in 32 patients (48%). The median progression-free survival was 4.2 months (95% CI, 1.8-6.6) and overall survival was 38.5 months (95% CI, 7.6-69.3). The mean (± standard deviation) IM Cmin at ED was 3552 (± 1540) ng/mL. IM Cmin was significantly increased after dose escalation (p &lt;0.001), and mean percent change from IM Cmin at SD was 162% (± 100). Body surface area (p=0.01), hemoglobin (p=0.001), and neutrophil count (p=0.006) were significant covariates for IM Cmin at ED in multivariate analysis. The group of quartiles of IM Cmin at ED and percent change was not associated with response and survival outcomes. However, grade 3-4 hematologic or grade 2-4 non-hematologic toxicity was observed in 9% (1/11) of patients in the lowest percent change quartile (Q1, &lt;90%) compared with 56% (18/32) in Q2 to Q4 (p=0.012), although absolute values were not associated with toxicity. Conclusions: In GIST patients treated with ED of IM, IM Cmin was not associated with response and survival. Clinically significant toxicity following dose escalation was correlated with percent change of IM Cmin, rather than absolute values. Monitoring of IM Cmin might help to predict or manage ED of IM induced toxicity.

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

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.

Abstract 5441: A rapid homogeneous immunoassay for the therapeutic drug management of imatinib in plasma using a novel selective monoclonal antibody

Abstract Objective: Imatinib is a potent and selective inhibitor of the Bcr-Abl and KIT protein tyrosine kinases. It is widely used for treatment of Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) and KIT-positive gastrointestinal stromal tumor (GIST). Studies have shown a significant inter-patient variability in imatinib trough concentrations up to 16 fold and a correlation between systemic exposure of the drug and clinical outcome. The current physical methods for measuring imatinib require specially trained personnel, larger sample sizes, are expensive, time consuming and not amenable for widespread use. The objective of this study is to develop an automated immunoassay that provides a rapid, simple and inexpensive method to routinely measure exposure of imatinib in patients undergoing chemotherapy. Methods: A library containing five novel and highly selective antibodies to imatinib were covalently linked to carboxyl-modified nanoparticles to develop a prototype automated homogenous assay for use on the Beckman Coulter AU®400 clinical analyzer which uses a two reagent system and 2 uL of plasma to quantitate imatinib. The degree of aggregation of nanoparticles, inversely proportional to the concentration of imatinib in a sample, was monitored at 600 nm. Total imprecision and linearity of the assay were evaluated by testing normal human plasma (NHP) pools spiked with different levels of imatinib. The background of the assay was also determined by measuring &amp;gt;100 NHP blank samples. Immunoassay selectivity was characterized by testing metabolites including N-desmethylimatinib and other structure-related compounds of imatinib for cross-reactivity at relevant physiological concentrations. Results: With a quantitative range from 100 to 4,000 ng/mL and instrument auto-dilution, plasma samples with imatinib concentrations up to 10,000 ng/mL could be determined using this assay. Time-to-first result was 11 minutes and 400 samples per hour could be measured using a stored calibration curve. The total imprecision of NHP pools spiked with imatinib at four concentrations across the assay range was &amp;lt;10% CV and the assay was linear from 100 to 4,000 ng/mL. The background of the assay was &amp;lt;50 ng/mL. The assay cross-reactivities to N-desmethylimatinib and other cross-reactants were determined to have insignificant impact on the quantitation of imatinib. Conclusion: This immunoassay is suitable for determining imatinib concentrations in plasma with the advantages of speed, small sample size, no sample pretreatment and application on automated instrumentation, providing a tool for optimization of imatinib plasma trough levels with pharmacokinetic-guided dosing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5441. doi:10.1158/1538-7445.AM2011-5441

Changes in imatinib plasma trough level during long-term treatment of patients with advanced gastrointestinal stromal tumors.

306 Background: Pharmacokinetic study in patients with gastrointestinal stromal tumors (GISTs) suggested that plasma concentrations of imatinib decrease following long-term exposure. We therefore measured changes in imatinib plasma trough levels (Cmin) after long-term exposure. Methods: Between November 2009 and May 2010, follow-up (FU) imatinib Cmin was measured in 65 patients who received the same dose of imatinib for at least 9 months after a previous baseline (BL) measurement. Total 244 blood samples were obtained (127 at BL and 117 at FU) and plasma level was measured by liquid chromatography-tandem mass spectrometry. Results: Median patient age was 54 years (range, 28–76 years) and 42 (64.6%) patients were male. Sixty-one (93.8%) patients were treated with 400 mg/day imatinib and 4 (6.2%) with 300 mg/day. The median interval from initiation of imatinib to BL test was 6.4 months (range, 0.5–66.6 months), and the median interval between BL and FU test was 13.1 months (range, 9.6–18.4 months). The mean ± standard deviation imatinib Cmin was significantly higher at FU than at BL (1442 ± 693 ng/mL vs 1221 ± 624 ng/mL, p&lt;0.001). The mean inter- and intra-subject variabilities were 49.2% and 25.5%, respectively, at BL, and 44.2% and 20.4%, respectively, at FU. Multivariate analysis showed a significant correlation between the ratio of FU to BL imatinib Cmin and that of albumin (r=-0.397, p=0.001). In per-sample analysis, imatinib Cmin was significantly correlated with age, hemoglobin, albumin, creatinine clearance, previous major gastrectomy and time between initiation of imatinib and plasma level tests. Conclusions: Steady-state imatinib Cmin did not decrease but remained stable in most GIST patients during long-term treatment. Changes in imatinib Cmin were associated with changes in albumin concentration. Monitoring of imatinib Cmin only for concerns about time-dependent decreases in imatinib exposure is not necessary. [Table: see text]

Changes in imatinib plasma trough level during long-term treatment of patients with advanced gastrointestinal stromal tumors: correlation between changes in covariates and imatinib exposure

A pharmacokinetic study in patients with gastrointestinal stromal tumors (GIST) suggested that imatinib plasma concentration may decrease following long-term exposure. We assessed changes in imatinib plasma trough levels (C(min)) during long-term treatment. Follow-up (FU) imatinib C(min) was measured in 65 patients who received the same dose of imatinib for at least 9 months after previous (initial) tests. After exclusion of 7 patients who had been treated with imatinib for over 2 years at the time of initial testing, 58 patients were included in this analysis. The median intervals from initiation of imatinib to initial testing and from initial to FU testing were 5.5 months (range, 0.5-24.0 months) and 13.0 months (range, 9.6-17.9 months), respectively. Mean inter- and intra-subject variability values were 47.7% and 20.9%, respectively, at initial measurements, and 45.2% and 19.4%, respectively, at FU. Mean FU imatinib C(min) (1,370 ± 661 ng/mL) was significantly higher than mean initial C(min) (1,171 ± 573 ng/mL; p = 0.003). Compared with initial C(min), FU C(min) was decreased in 22 patients and increased in 36, with median changes of 13% and 32%, respectively. Multivariate analysis showed a significant correlation between the ratio of FU to initial imatinib C(min) and that of albumin (r = -0.39, p = 0.003). During long-term treatment, imatinib C(min) did not decrease significantly but remained stable or increased in most patients. Changes in imatinib C(min) were associated with changes in albumin concentration. Monitoring of imatinib C(min) only for concerns about time-dependent increases in imatinib clearance is not necessary.

Imatinib plasma levels: correlation with clinical benefit in GIST patients

Imatinib plasma levels: correlation with clinical benefit in GIST patients

Cross-Sectional Study of Imatinib Plasma Trough Levels in Patients With Advanced Gastrointestinal Stromal Tumors: Impact of Gastrointestinal Resection on Exposure to Imatinib

Imatinib plasma trough levels (C(min)) have been reported to correlate with treatment outcomes in patients with gastrointestinal stromal tumors (GISTs). We therefore have evaluated the correlation between imatinib C(min) and the clinical characteristics of patients with GIST. Steady-state imatinib C(min) in 107 patients with GIST who were taking imatinib 300 to 800 mg/d was measured. In patients treated with imatinib 400 (n = 92), 300 (n = 7), 600 (n = 2), or 800 (n = 11) mg/d, imatinib C(min) was 1,305 +/- 633 ng/mL, 1,452 +/- 830 ng/mL, 1,698 +/- 725 ng/mL, and 3,330 +/- 1,592 ng/mL, respectively. Of the 92 patients treated with 400 mg/d imatinib, 59 patients (63%) were men; the median age was 55 years (range, 28 to 76 years), and the median duration of imatinib use before sampling was 8.8 months (range, 0.5 to 67.6 months). The mean inter- and intrapatient variability rates were 44.7% and 26.5%, respectively. In univariate analyses, high C(min) was correlated with advanced age (P = .02), low creatinine clearance (P = .001), low hemoglobin (P = .03), and low albumin (P < .001) concentrations. Imatinib C(min) was also significantly lower in patients with (n = 18; 942 +/- 330 ng/mL) than without (n = 74; 1,393 +/- 659 ng/mL) major (ie, total or subtotal) gastrectomy (P = .002). In multivariate analysis, albumin (P = .001) concentrations, creatinine clearance (P = .002), and major gastrectomy (P = .003) were significantly correlated with C(min). In patients with GIST, imatinib C(min) at steady state was significantly associated with albumin concentration, creatinine clearance, and previous major gastrectomy. Although its clinical impact is unclear at present time, monitoring of imatinib C(min) might be particularly important for optimal treatment with imatinib in patients who have undergone major gastrectomy.

Imatinib (IM) Pharmacokinetic (PK) Exposure and Its Correlation with Clinical Outcome in Patients with Chronic-Phase Chronic Myeloid Leukemia (CML-CP) for 400 Mg and 800 Mg Daily Doses (Tyrosine Kinase Dose Optimization Study [TOPS

Background: Correlation between IM plasma level and clinical response has been previously reported [Larson et al., Picard et al.]. TOPS is an open-label, randomized, multicenter Phase III study investigating whether 800 mg of IM (400 mg twice daily) results in an improved efficacy compared with 400 mg daily IM in newly diagnosed, previously untreated CML-CP. This analysis reports IM trough plasma levels (Cmin) at both doses and their correlation with clinical response and safety parameters.Methods: IM PK trough samples were collected at time 0 (predose), and following 1, 6, 9, and 12 month treatment for both 400 mg/day (mg/d) and 800 mg/d arms. Plasma concentrations of IM and CGP74588 (major metabolite) were determined by a validated LC/MS/MS (liquid chromatography and tandem mass spectrometry) method. Correlation of IM exposure with clinical response (major molecular response [MMR] rates and time to first MMR) was assessed by grouping patients into quartiles based on their measured IM Cmin levels in month 1. For correlation with frequency of adverse events [AEs], an average Cmin (aCmin) over 12 months corrected for dose intensity was used for the analysis. Correlations were assessed for the entire evaluable population and for each dose group separately.Results: IM PK exposure was proportional to dose and stable over time. For the 400 mg/d dose (n=78–87), the median IM Cmin values at month 1, 6, 9, and 12 were 1190, 1060, 1210, and 1295 ng/mL, respectively; and for the 800 mg/d dose (n=148–167) the corresponding Cmin values for each month were 2720, 2340, 2170, and 2150 ng/mL, respectively. The intra-patient variability (CV%) was low and similar between the 400 mg/d and 800 mg/d doses, 25% and 27%, respectively. The inter-patient variability (CV%) was 38% for 400 mg/d and 58% for 800 mg/d. Despite this inter-patient variability there was a strong correlation between IM Cmin at month 1 (Table 1) and time to MMR or MMR at 3, 6, 9 and 12 months.Table 1: MMR rates over 12 months based on month 1 IM Cmin quartiles for evaluable patients with PK dataMMR Rate* (%)Relative benefit (Fishers Exact Test p-value)Month of treatment (No. of evaluable patients)IM Cmin Q1 <1165 ng/mLIM Cmin Q2-Q3 1165–3180 ng/mLIM Cmin Q4 >3180 ng/mLQ2-Q3 vs Q1Q4 vs Q1Month 3 (218)0/54 (0%)15/108 (14%)10/56 (18%)NA (0.0027)NA (0.0013)Month 6 (208)8/51 (16%)38/103 (37%)22/54 (41%)2.35 (0.0084)2.60 (0.0052)Month 9 (212)21/57 (37%)60/103 (58%)29/52 (56%)1.58 (0.013)1.51 (0.0561)Month 12(214)21/56 (38%)62/107 (58%)30/51 (59%)1.55 (0.0142)1.57 (0.0338)*No. of patients achieving MMR/total number of patients evaluable at each visitBased on the evaluable population at month 12, patients with higher Cmin at month 1 (>1165 ng/mL, Q2-Q4) achieved MMR faster than patients with lower Cmin (<1165 ng/mL, Q1) (P=0.0149). The MMR rate at 12 months was 58% for Q2-Q4 group and 38% for Q1 group (P=0.0263). In the 400 mg/d group, the MMR rate at month 12 was 24% for patients with Cmin below 851 ng/mL (Q1 for 400 mg/d), compared to 56% for patients with Cmin above 851 ng/mL (Q2-Q4; P=0.0207). In the 800 mg/d arm, the overall MMR at 12 month was 50%, and no significant differences were observed between different Cmin quartiles, although it should be noted that the majority of patients (88%) at this high dose level achieved a Cmin above 1165 ng/mL as compared with 52% for the 400 mg/d group. Using aCmin over 12 months as a rough estimate of exposure including dose changes, a slightly higher incidence of all grade AEs for the most frequently reported AEs such as rash, diarrhea, fatigue, and all cause edema, was observed in patients in the highest quartile but no significant differences in the frequency of grade 3/4 AEs were observed.Conclusion: In TOPS, IM plasma trough level was proportional to dose and stable over time despite a high inter-patient variability which may have been attributable to dose changes. Patients with a IM Cmin in the lowest quartile showed a lower MMR rate at 12 months, whereas patients in the highest aCmin quartile showed a higher frequency of all grades of some AEs. The TOPS trial confirms previous observations that IM Cmin of approximately <1000 ng/mL are associated with poorer outcomes. Monitoring IM levels can provide an added benefit to CML patients on IM to achieve the best clinical outcomes.