Imatinib Plasma Concentrations Research Articles

Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting

BackgroundImatinib has dramatically improved the prognosis of advanced gastrointestinal stromal tumours (GISTs). Clinical trial data showed that patients with trough imatinib plasma concentrations (Cmin) below 1100 ng/ml (quartile 1) had shorter time to progression, but no threshold has been defined.The main objective of this study was to investigate in advanced GIST whether a Cmin threshold value associated with a longer progression-free survival (PFS) could be specified. This would be the first step leading to therapeutic drug monitoring of imatinib in GIST. Patients and methodsAdvanced GIST patients (n=96) treated with imatinib 400 mg/d (41 stomach, 34 small bowel, and 21 other primary site localisations) were prospectively included in this real-life setting study. Routine plasma level testing imatinib (Cmin) and clinical data of were recorded prospectively. ResultsSmall bowel localisation was associated with an increased relative risk of progression of 3.09 versus stomach localisation (p=0.0255). Mean Cmin (±standard deviation) was 868 (±536) ng/ml with 75% inter-individual and 26% intra-patient variability. A Cmin threshold of 760 ng/ml defined by log-rank test was associated with longer PFS for the whole population (p=0.0256) and for both stomach (p=0.043) and small bowel (p=0.049) localisations when analysed separately. Multivariate Cox regression analysis found that Cmin above 760 ng/ml was associated with 65% reduction risk of progression (p=0.0271) in the whole population independently of the anatomical localisation. ConclusionConcentration of imatinib significantly influences duration of tumour control treatment in GIST patients with a Cmin threshold of 760 ng/ml associated with prolonged PFS in real-life setting.

SY10-1 - Pharmacokinetic Issues on Cancer Pharmacotherapy

Efficacy of cancer pharmacotherapy depends upon drug exposure to the body and responsiveness of the tumor to the drug treatment. Drug exposure is determined by pharmacokinetics and dose, whereas responsiveness is intrinsically variable by tumor heterogeneity. Recently, a number of molecular targeting agents are used as promising therapy for cancers, and most of them are coupled with particular diagnostics which can predict treatment response. These diagnostics examine somatic mutations of individual cancers, and are used to distinguish responders and non-responders before choosing right patients and right drugs.On the other hand, lower drug exposure to the body also leads to insufficient efficacy. Although most of pharmacokinetic studies in the past were related to the toxicity of oncologic agents, a number of important evidences have been published recently on exposure-effect relationships for molecular targeting, chemotherapeutic and hormonal agents. For example, efficacy of tyrosine kinase inhibitor, imatinib in chronic myelogenous leukemia (CML) or gastrointestinal stromal tumor (GIST) depended on plasma concentration of imatinib. Therefore, therapeutic drug monitoring (TDM) of imatinib has been introduced into clinical practice in Japan. Usefulness of TDM was also reported to improve the efficacy and safety of continuous 5-fluorouracil therapy. Individual variation in the capability of hepatic activation creates inter-individual variation in efficacy of the tamoxifen treatment. CYP2D6 is a key enzyme responsible for converting tamoxifen to active metabolites, endoxifen and 4-hydroxytamoxifen. The breast cancer patients who carry decreased-functional alleles of CYP2D6 showed lower plasma concentrations of endoxifen compared to patients with normal functional allele, probably resulting in worse clinical outcome in tamoxifen therapy. Knowledge of the exposure-response relationships becomes quite important for improving cancer pharmacotherapy.

Therapeutic Drug Monitoring of Imatinib in Gist Patients

ABSTRACT Aim: Imatinib is a drug of choice for the treatment of gastrointestinal stromal tumors (GIST), and some studies suggest that a minimum plasma concentration (Cmin) of 1 mg/L should be obtained to ensure the achievement of maximum therapeutic benefit from the drug. However, the pharmacokinetics of imatinib is widely variable among patients and a therapeutic drug monitoring (TDM) should be adopted. Therefore, the rationale of the study was to evaluate the feasibility of a TDM protocol in GIST patients and any possible correlation with treatment efficacy and/or toxicity. Methods: Twelve GIST patients, 6 men and 6 women (median age and range, 65.9 and 49-71.7 years and 65.3 and 52.8-80.4 years, respectively), receiving imatinib at the daily median dose of 400 mg (range, 200-800 mg/day), were enrolled. Blood samples were obtained during follow-up visits at any time after drug intake and the time elapsed between imatinib administration and blood withdrawal was carefully recorded. Plasma concentrations of imatinib were measured by a commercially-available kit (Chromsystems, Munich, Germany), then Cmin values were predicted adopting a noncompartmental pharmacokinetic analysis. Finally, clinical data regarding response and tolerability were recorded. Results: Cmin values were higher in women (mean±SD, 1.730±0.867 mg/L) than in men (0.975±0.584 mg/L, p=0.111), and there was a linear correlation (r=0.641, p Conclusions: Although imatinib is characterized by a good tolerability and a linear relationship between daily dose and plasma concentrations, an interindividual varability in drug disposition exists and occurrence of toxicities may be associated with the highest Cmin values, hence strenghtening the role of TDM protocols in GIST patients receiving imatinib. Disclosure: All authors have declared no conflicts of interest.

Plasma and Intracellular Imatinib Concentrations in Patients With Chronic Myeloid Leukemia

Imatinib (Gleevec, STI-571), a 2-phenylaminopyrimidine-type competitive inhibitor of Bcr-Abl kinase, is the current frontline therapy for patients with chronic myeloid leukemia, and it induces durable responses and prolonging event-free and progression-free survival. Monitoring imatinib trough plasma concentration is a simple and rapid way to determine if the drug exposure exceeds the clinical efficacy threshold (1 mcg/mL). Because the target enzyme is located within cells, adequate drug intracellular concentrations are needed to inhibit its function. Chromatographic methods were used to quantify imatinib concentrations in both plasma and peripheral blood mononuclear cells collected from adult patients with chronic myeloid leukemia at the Department of Hematology. Samples were collected at steady state, and trough concentrations (24 ± 2 hours after last drug intake) were evaluated. Associations between variables were tested using the Pearson test; results are presented as mean (±SD). Thirty-five samples from 24 patients were collected; patients were mainly men (16, 66.7%), aged 60 years old (±13.1) and with a body mass index of 24.8 (±4.4). A positive and significant correlation (r = 0.203; P = 0.027) was found between imatinib plasma and intracellular concentrations. The observed correlation between plasma and intracellular imatinib concentrations suggests that they may be used to monitor drug exposure and treatment efficacy.

Plasma Concentrations of Tyrosine Kinase Inhibitors Imatinib, Erlotinib, and Sunitinib in Routine Clinical Outpatient Cancer Care

The objectives of this study were to evaluate the plasma concentrations of the tyrosine kinase inhibitors (TKIs), imatinib, erlotinib, and sunitinib, in a cohort of patients with cancer in routine clinical practice and to find the possible factors related to plasma concentrations below the target level. An observational study was performed in an unselected cohort of patients using TKIs for cancer treatment. Randomly timed plasma samples were drawn together with regular laboratory investigations during routine outpatient clinic visits. The plasma concentrations of TKIs were determined using a validated high-performance liquid chromatography coupled with tandem mass spectrometry detection method. Trough concentrations were estimated using the interval between the last dose intake and blood sampling and the mean elimination half-life of the TKIs and were compared with target trough concentrations. Outpatient medical records were reviewed to collect data on patient- and medication-related factors that could have contributed to the variation in TKI plasma concentrations. Only 26.8%, 88.9%, and 51.4% of the calculated trough plasma concentrations of imatinib, erlotinib, and sunitinib samples, respectively, reached the predefined target concentration (imatinib: 1100 ng/mL, erlotinib: 500 ng/mL, and sunitinib: 50 ng/mL). Interpatient variability was high with coefficients of variation of 39.1%, 40.1%, and 29.2% for imatinib, erlotinib, and sunitinib, respectively. High variation in plasma concentrations could only partly be explained by patient- or medication related factors. Almost half of the plasma concentrations in the outpatient population seemed to be below the target level with a risk of treatment failure. It is not possible to predict which patients are at a risk of plasma concentrations below the target level based on patient- or medication-related factors. Thus, therapeutic drug monitoring could play a crucial role in routine cancer care to identify patients that are in need of individual adjusted dosages. Further research is required to investigate the safety and efficacy of therapeutic drug monitoring.

CD117 (c-kit) Expression On CD34+ Cells Participates In The Cytogenetic Response To Imatinib In CML Patients In First Chronic Phase

BackgroundChronic myeloid leukemia (CML) biology seemed to be perfectly explored especially at the beginning of tyrosine kinase inhibitors era (TKI). Later years with imatinib and second generation TKI showed variety of resistance mechanisms and it became obvious bcr-abl chimeric gene is not the only enemy to fight. Some studies assumed the decreased rate of programmed cell death (apoptotic) to be the primary mechanism by which BCR-ABL effects expansion of the leukemic clone in CML. Other studies showed the important role of patients adherence in achieving best possible response for imatinib. Imatinib plasma level was recognized as a useful tool for adherence evaluation. In this study we evaluate the expression of apoptotic marker, Annexin V in CD34+CD117+ cells of CML patients in first chronic phase treated with imatinib and try to find the correlation between this expression and cytogenetic response or imatinib plasma level. PatientsThe group of 54 CML patients (F/M = 30/24, median age, 50.5) in first chronic phase treated with imatinib (400 mg daily) was analyzed. The median time of treatment was 17 months (min. 12 months, max. 24 months. Only patients with the conventional translocation (Philadelphia chromosome) without additional chromosomal aberrations or clonal evolution during the treatment period were included in the study. Patients were categorized according to ELN criteria for cytogenetic response: complete cytogenetic response (CCyR) vs. no cytogenetic response (NCyR, defined as everything less than CCyR), and for molecular response: major molecular response (MMR) vs. no molecular response (NMR). ResultsIn the cohort of 54 patients, 39 achieved CCyR in a median time of 12 months. Among these patients, 30 achieved MMR within the same time. Bone marrow CD34 positive cells were assessed for expression of CD117 and Annexin V in all groups of patients (CCyR with MMR, CCyR with NMR, and NCyR). The mean percentage of CD34+CD117+ cells was significantly higher in the NCyR group (7.67±5.62) in comparison with the CCyR group (2.27±1,78; p=0.002). The difference between MMR and NMR subgroups was not significant. While analyzing the CD34+CD117+ population, we found a significantly higher percentage of apoptotic cells (Annexin V positive) in the CCyR group (4.65±4.55) than in the NCyR group (1.67±1.22; p=0.004). Once again this difference was not significant between MMR and NMR subgroups. Serum imatinib levels were quantified in both CCyR and NCyR groups. We found higher values in the CCyR group (1244 μg/l±599) than in the NCyR group (1192 μg/l±593) but this difference was insignificant. ConclusionsIt was recently reported that c-kit must be inhibited to allow apoptosis of CML cells. Our results also correspond with these data. Not only was a lower percentage of CD34+CD117+ cells found in the CCyR group, but the fraction of these cells that were apoptotic was significantly greater compared with the NCyR group. Although other studies have indicated that trough plasma concentration of imatinib reflects clinical response in chronic phase of CML, we did not observe this. Our results showed higher imatinib levels in CCyR, but these data were insignificant. In conclusion, our results indicate that to achieve optimal treatment response in CML patients, c-kit kinase inhibition may be a requirement for successful proapoptotic activity of imatinib. Disclosures:No relevant conflicts of interest to declare.

Calcium carbonate does not affect imatinib pharmacokinetics in healthy volunteers

Imatinib mesylate (Gleevec(®)/Glivec(®)) has revolutionized the treatment of chronic myeloid leukemias and gastrointestinal stromal tumors, and there is evidence for an exposure response relationship. Calcium carbonate is increasingly used as a calcium supplement and in the setting of gastric upset associated with imatinib therapy. Calcium carbonate could conceivably elevate gastric pH and complex imatinib, thereby influencing imatinib absorption and exposure. We aimed to evaluate whether use of calcium carbonate has a significant effect on imatinib pharmacokinetics. Eleven healthy subjects were enrolled in a 2-period, open-label, single-institution, randomized crossover, fixed-schedule study. In one period, each subject received 400 mg of imatinib p.o. In the other period, 4,000 mg calcium carbonate (Tums Ultra(®)) was administered p.o. 15 min before 400 mg of imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were assayed by LC-MS; data were analyzed non-compartmentally and compared after log transformation. Calcium carbonate administration did not significantly affect the imatinib area under the plasma concentration versus time curve (AUC) (41.2 μg/mL h alone vs. 40.8 μg/mL h with calcium carbonate, P = 0.99), maximum plasma concentration (C(max)) (2.35 μg/mL alone vs. 2.39 μg/mL with calcium carbonate, P = 0.89). Our results indicate that the use of calcium carbonate does not significantly affect imatinib pharmacokinetics.

Therapeutic drug monitoring for imatinib: Current status and Indian experience

Imatinib is the current gold standard for treatment of chronic myeloid leukemia (CML). Recent pharmacokinetic studies have shown considerable variability in trough concentrations of imatinib due to variations in its metabolism, poor compliance, or drug-drug interactions and highlighted its impact on clinical response. A trough level close to 1000 ng/mL, appears to be correlated with better cytogenetic and molecular responses. Therapeutic Drug Monitoring (TDM) for imatinib may provide useful added information on efficacy, safety and compliance than clinical assessment alone and help in clinical decision making. It may be particularly helpful in patients with suboptimal response to treatment or treatment failure, severe or rare adverse events, possible drug interactions, or suspected nonadherence. Further prospective studies are needed to confirm relationship between imatinib plasma concentrations with response, and to define effective plasma concentrations in different patient populations.

Imatinib plasma concentrations during long-term effective treatment of metastatic gastrointestinal stromal tumor.

10543 Background: Imatinib concentrations at one month after the start of imatinib have shown an association with clinical benefit in pts with gastrointestinal stromal tumors (GISTs) and a significant decrease of 30% within twelve months. This retrospective study investigated imatinib plasma concentrations in pts with metastatic GISTs in a long-term (≥2 years) effective treatment. Methods: 31 metastatic GIST pts, who had been treated with imatinib for two or more years in our hospital, were enrolled in this study. 11 pts were excluded because of adjuvant setting (n=5) and rejection to concentration testing (n=6). 20 pts were included in this study. GISTs were immunohistochemically diagnosed, and radiologically assessed as effective GIST by Choi’s criteria without relapse. Results: 10 pts were male, median age was 63 years (range, 31-84), and median imatinib exposure time was 3.5 year (range, 2-12). The median plasma concentration was 1093 ng/ml (range, 417-2091) and minimal level after at least five years was 789 ng/ml. imatinib concentration has no significant correlation with age, gender, gastrectomy, leukocyte count, platelet count, serum albumin, serum creatinine, cholesterol, and duration of imatinib exposure. Body surface area (BSA) isn’t directly associated with imatinib dose; median BSA of pts taking 300mg imatinib was 1.560 m2 and that of 400mg 1.595 m2, but minimal BSA of 400mg imatinib was 1.560 m2, which is higher than the minimum of 300mg. Conclusions: Plasma concentrations of long-term (≥2 years) response pts was scattered, but one of longer-term (≥5 years) response pts were more than 789 ng/ml. Effective imatinib plasma level might be more than 789 ng/ml and 400mg imatinib may be recommended for a pt with BSA(≥1.56 m2).

Demonstration of gender-specific variability in a pharmacokinetic (PK) analysis of the PERSIST-5 trial of adjuvant imatinib (IM) for patients with primary gastrointestinal stromal tumor (GIST) at significant risk of recurrence.

10538 Background: ThePERSIST-5 phase II trial is evaluating 5 years of adjuvant IM therapy in patients with resected GIST at significant risk of recurrence. This analysis studied the effect of chronic therapy on steady-state trough levels in patients who received IM for up to 24 months to evaluate potential PK variations. Methods: Eligible patients were adults with KIT+ primary GIST who were considered to be at significant risk for recurrence (primary tumor any site ≥2 cm andmitotic rate ≥5/50 high-power fields, or non-gastric primary GIST ≥5 cm) without metastases. R0 resection of primary GIST was performed ≤12 weeks prior to the first IM dose. Patients are to receive oral IM 400 mg/day for up to 5 years or until progression, relapse, or intolerance. Plasma samples for PK analysis were collected at 1, 4, 12, and 24 months. IM plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. Results: In-study assay performance (%CV) was ≤9.6% and bias was -1.3% to 5.2%. IM concentrations ranged from below quantifiable limits to 4798 ng/mL. After daily IM doses for up to 12 months (or 24 months in 3 patients), IM trough levels remained constant over time. The range of IM trough levels (mean ± SD) was 957 ± 750 ng/mL to 1219 ± 822 ng/mL at month 1, and 727 ± 430 ng/mL to 996 ± 405 ng/mL at month 12. Inter-patient variability was 40.7-78.4%. There was no significant difference in IM trough levels between months 1 and 4, 1 and 12, or 4 and 12. Trough levels did not significantly differ by location of GIST. Most notably, mean IM trough concentrations were on average ~33% higher in females vs males. Conclusions: In this study,IM trough levels remained relatively unaltered in patients with high-risk GIST who received adjuvant IM for 1 year. The 33% higher mean trough levels in females warrants further study for clinical decision making. Clinical trial information: NCT00867113. [Table: see text]

Gemfibrozil Impairs Imatinib Absorption and Inhibits the CYP2C8-Mediated Formation of Its Main Metabolite

Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, gemfibrozil reduced the peak plasma concentration (Cmax) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the Cmax and area under the plasma concentration-time curve (AUC0-∞) of N-desmethylimatinib by 56 and 48% (P < 0.001), respectively, whereas the AUC0-∞ of imatinib was unaffected. Furthermore, gemfibrozil reduced the Cmax/plasma concentration at 24 h (C24 h) ratios of imatinib and N-desmethylimatinib by 44 and 17% (P < 0.05), suggesting diminished daily fluctuation of imatinib plasma concentrations during concomitant use with gemfibrozil. Our findings indicate significant participation of CYP2C8 in the metabolism of imatinib in humans, and support involvement of an intestinal influx transporter in imatinib absorption.

Systematic Review of Population Pharmacokinetic Analyses of Imatinib and Relationships With Treatment Outcomes

Several population pharmacokinetic (PPK) analyses of the anticancer drug imatinib have been performed to investigate different patient populations and covariate effects. The present analysis offers a systematic qualitative and quantitative summary and comparison of those. Its primary objective was to provide useful information for evaluating the expectedness of imatinib plasma concentration measurements in the frame of therapeutic drug monitoring. The secondary objective was to review clinically important concentration-effect relationships to provide help in evaluating the potential suitability of plasma concentration values. Nine PPK models describing total imatinib plasma concentration were identified. Parameter estimates were standardized to common covariate values whenever possible. Predicted median exposure (C min) was derived by simulations and ranged between models from 555 to 1388 ng/mL (grand median: 870 ng/mL and interquartile "reference" range: 520-1390 ng/mL). Covariates of potential clinical importance (up to 30% change in pharmacokinetic predicted by at least 1 model) included body weight, albumin, α1 acid glycoprotein, and white blood cell count. Various other covariates were included but were statistically not significant or seemed clinically less important or physiologically controversial. Concentration-response relationships had more importance below the average reference range and concentration-toxicity relationships above. Therapeutic drug monitoring-guided dosage adjustment seems justified for imatinib, but a formal predictive therapeutic range remains difficult to propose in the absence of prospective target concentration intervention trials. To evaluate the expectedness of a drug concentration measurement in practice, this review allows comparison of the measurement either to the average reference range or to a specific range accounting for individual patient characteristics. For future research, external PPK model validation or meta-model development should be considered.

Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours

Total imatinib concentrations are currently measured for the therapeutic drug monitoring of imatinib, whereas only free drug equilibrates with cells for pharmacological action. Due to technical and cost limitations, routine measurement of free concentrations is generally not performed. In this study, free and total imatinib concentrations were measured to establish a model allowing the confident prediction of imatinib free concentrations based on total concentrations and plasma proteins measurements. One hundred and fifty total and free plasma concentrations of imatinib were measured in 49 patients with gastrointestinal stromal tumours. A population pharmacokinetic model was built up to characterize mean total and free concentrations with inter-patient and intrapatient variability, while taking into account α1 -acid glycoprotein (AGP) and human serum albumin (HSA) concentrations, in addition to other demographic and environmental covariates. A one compartment model with first order absorption was used to characterize total and free imatinib concentrations. Only AGP influenced imatinib total clearance. Imatinib free concentrations were best predicted using a non-linear binding model to AGP, with a dissociation constant Kd of 319 ng ml(-1) , assuming a 1:1 molar binding ratio. The addition of HSA in the equation did not improve the prediction of imatinib unbound concentrations. Although free concentration monitoring is probably more appropriate than total concentrations, it requires an additional ultrafiltration step and sensitive analytical technology, not always available in clinical laboratories. The model proposed might represent a convenient approach to estimate imatinib free concentrations. However, therapeutic ranges for free imatinib concentrations remain to be established before it enters into routine practice.

Long-term Prospective Population PK Study in GIST Patients—Letter

The study conducted by Eechoute and colleagues ([1][1]) revealed additional and useful information regarding imatinib pharmacokinetics. By accumulating plasma imatinib concentrations in 50 patients for 12 months, they observed significantly lower concentrations after 90 days of treatment. It was

In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia.

Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

Treatment of advanced gastrointestinal stromal tumors in patients over 75 years old: clinical and pharmacological implications

Data about the patterns of care and the specific outcome of elderly patients with advanced gastrointestinal stromal tumors (GISTs) are almost nonexistent. Between 2001 and 2009, 44 patients ≥75 years old with advanced GISTs started first-line imatinib (400 mg/day) in seven participating institutions. Clinical data were collected by reviewing medical records and were entered in a comprehensive database. During the same period, 160 patients with advanced GIST (136 patients <75 years old, 24 patients ≥75 years old) had access to an imatinib blood level testing program. Imatinib plasma concentration (patient dose 400 mg/day) tests were centralized in a single laboratory. Median age was 78 years old (range 75-86). Thirty-six patients (82 %) experienced at least one adverse event (Table 2). Drug-related adverse events were mainly of grades 1 and 2 and were medically manageable. Permanent dose reduction (200-300 mg/day) was required for 20 patients (45.5 %) and was significantly more frequent for patients with performance status (PS) ≥2: 33.5 versus 8.5 %, p = 0.04. Eight patients (18 %) required imatinib interruption for intolerance. Median PFS was 34.4 months (95 % CI 11.5-57.4) (Fig. 1). Median overall survival (OS) was 50.3 months (95 % CI 37-63.5). Performance status <2 was the sole pre-therapeutic factor associated with improved OS. No correlation was found between comorbidities and tolerance or outcome. Imatinib trough plasma concentrations increase with age, although this correlation did not reach statistical significance. First-line imatinib is a feasible and effective treatment in patients with advanced GISTs ≥75 years. Aging seems to have only a moderate impact on imatinib pharmacokinetics. Overall survival is similar to that of younger patients. Comorbidities did not result in increased incidence of toxicity. Careful follow-up regarding tolerance issues should be considered in elderly patients with poor PS.

Correlation Between Imatinib Trough Concentration and Long-Term Tolerability in CML Patients

AbstractAbstract 3751 Background and Purpose:The introduction of imatinib to the treatment regimen of chronic myeloid leukemia (CML) has markedly changed its outcome. Several reports have shown that the efficacy of imatinib correlates with the trough plasma concentration in CML patients. However, little is known about the correlation between plasma concentration and long-term outcomes, including adverse effects. We analyzed the correlation between long term tolerability and plasma concentration in Japanese patients. Patients:Forty-three patients with chronic phase CML who had good adherence with daily 300mg (n=8) or 400mg (n=35) imatinib administration at hospitals in our study group were enrolled in this study. The median age of patients starting imatinib was 57 years (range 15–82). Imatinib was started between Dec. 2001 and May 2007. Plasma trough concentration was examined on a day between Nov. 2007 and Aug. 2008. Median time from the start of imatinib until the plasma assay was 1548 days (range 91–2390). Results:Clinical data were reviewed in Sep 2011. We excluded patients who had been switched from imatinib to a second tyrosine kinase inhibitor (TKI) despite major molecular response (MMR). Median plasma concentration was 925 ng/ml (range 200–3280). Median follow-up was 2632 days (range 884–3496) and median follow-up after the plasma assay was 1216 days (range 361–1323). We divided the patients into two groups: the low plasma concentration group (<925ng/ml n=22) and high plasma concentration group (>925ng/ml n=21). Overall survival and achievement of complete molecular response (negative by RT-PCR) did not differ between the two groups. We defined all death, progression, switch to a second TKI and imatinib dose reduction as events. Also we defined death by adverse effect, imatinib dose reduction or switch to a second TKI due to adverse effects as intolerance-related events and progression, switch to a second TKI due to failure of achieve MMR or loss of MMR as efficacy-related events. Event-free survival (EFS) showed no difference between the two groups. However cumulative incidence of intolerance-related event was significantly higher in the high plasma concentration group than in the low plasma concentration group (whole observation period, p=0.02 by log-rank test; observation period after the plasma assay, p=0.01 by log-rank test). Grade 3 or 4 anemia occurred in 4 patients only in the high plasma concentration group. Cumulative incidence of efficacy-related event was slightly higher in the low plasma concentration group than the high plasma concentration group (whole observation period, p=0.06 by log-rank test; observation period after the plasma assay p=0.05 by log-rank test). Conclusion:Trough imatinib plasma concentration at steady-state after initiation of therapy has been demonstrated to have correlation with the early efficacy of imatinib. Our findings suggest that imatinib plasma concentration also correlates with intolerance or adverse effect in long-term clinical observation. Although further studies are required to confirm the current data prospectively, imatinib plasma level testing seems to be helpful to optimize clinical outcomes for patients with CML. Disclosures:No relevant conflicts of interest to declare.

Association Between CYP3A4 Polymorphisms, Trough Imatinib Plasma Concentration and Cytogenetic Response in Chronic Phase Chronic Myeloid Leukemia (CML-CP)

AbstractAbstract 3788 Introduction:Imatinib mesylate has demonstrated excellent efficacy as first-line therapy for treatment of chronic phase chronic myelogenous leukemia (CML-CP). The drug has a high inter-patient variability in pharmacokinetics (PK), and several factors are presumed to influence its PK. Imatinib is a substrate of CYP3A4 and CYP3A5 enzymes. However, the clinical significance of its metabolism on pharmacokinetics and therapeutic response is still unclear. Significantly higher in vivo CYP3A activity was reported recently in patients achieving complete molecular response than those who did not in a small cohort study. Several investigators in the past have tried to optimize imatinib dosing based on trough levels after the fourth treatment week. Picard S et al (Blood, 2007) showed that threshold plasma concentration of 1002 ng/ml on day 29 was associated with higher incidence of major molecular response. The primary objective of this study was to evaluate the association between CYP3A4 polymorphisms, trough plasma concentration of imatinib on day 8 and day 29 of treatment, and cytogenetic response. The secondary objective was to evaluate the potential of early (day 8) trough level monitoring to discriminate between responders and non-responders. Methods:All patients received standard 400 mg OD dose of imatinib. A single blood sample was collected on day 8 and day 29 prior to imatinib dosing for the determination of trough plasma concentration. Imatinib level was determined using High Performance Liquid Chromatography (HPLC). Cytogenetic response was assessed at 3 monthly intervals by Fluorescence In Situ Hybridization (FISH). Complete cytogenetic response (CCR) was defined as 0% of Philadelphia chromosome–positive cells in the bone marrow aspirate. Pharmacogenetic sample was collected from each patient at the beginning of the study to look for CYP3A4 polymorphism. Genotyping was carried out for *4 (rs55951658), *5 (rs55901263) and *18 (rs28371759) variants by PCR-RFLP technique. About 10% samples were chosen randomly for direct sequencing to confirm the PCR-RFLP findings. Median imatinib concentration in the CCR and non CCR groups was compared using non-parametric Mann-Whitney test. Receiver Operating Characteristic (ROC) curve analysis was performed to assess the discrimination potential of trough imatinib plasma levels for complete cytogenetic response (CCR). Results:Ninety eight patients were enrolled on this study, 70 males and 28 females. The median age was 33 years (Range 6 – 71 years). High interpatient variability in the trough concentration of imatinib was observed (Coefficient of variation = 64% and 56% for day 8 and day 29 respectively). However, none of the patients were found to have *4, *5 or *18 variant alleles. Genotype–PK or genotype-response association could not be evaluated as a result. Data on cytogenetic response at 12 months was available for 75 patients (60 CCR, 15 without CCR), 46 of whom also had trough imatinib levels measured on day 8 and day 29 (36 CCR, 10 without CCR). Median day 8 and day 29 trough concentrations were not significantly different in the group with CCR (1.71 and 1.91 μg/mL respectively) and the group without (1.31 and 1.64 μg/mL respectively). Regarding the discrimination potential of trough levels for CCR, day 8 concentrations failed to discriminate between responders and non-responders, whereas for the Day 29 levels, the area under the ROC curve (AUC) was 0.554, with best sensitivity (75%) and specificity (61%) at plasma threshold of 1.69 μg/mL. Conclusion:In this cohort of patients, common CYP3A4 variants did not contribute to the high inter-patient variability of imatinib levels. Early monitoring on Day 8 failed to discriminate responders from non-responders. Day 29 levels are a better predictor of complete cytogenetic response as shown in previous studies. Disclosures:No relevant conflicts of interest to declare.

EL20 - PK/PD of Molecular-Targeting Drugs

ABSTRACT Pharmacokinetics (PK) and pharmacodynamics (PD) are frameworks to quantitatively describe the dose exposure–response (efficacy and safety) relationships. PK/PD provides an important rationale for dose setting of molecular targeting drugs to which the empiric MTD paradigm is not applicable. The dosage regimen of trastuzumab was designed to achieve and maintain serum trough concentrations >20 µg/ml. This target concentration was decided based on growth inhibition of human breast cancer cell line in vitro and nude mice xenograft model in vivo. Therefore, neither MTD determination nor dose–response analysis in clinical studies was conducted. A more sophisticated strategy was applied for development of trastuzumab-DM1 (T-DM1), using animal experimental data, population PK/PD modeling and tumor response model. Based on this modeling, early clinical trials of T-DM1 were designed to target the translational pharmacology parameter which is a drug concentration with no tumor growth. PK/PD modeling and simulation together with tumor progression model are expected to be an alternative or complement to the empiric MTD paradigm in early phase, particularly first in human studies for molecular targeting drugs. The PK/PD concept is also applied to tyrosine kinase inhibitors. In the development of sunitinib, pharmacologically effective concentration was determined by preclinical mice in vivo study which measured time and dose dependency of target receptor phosphorylation and VEGF-induced vascular permeability. The phase 1 clinical trial was designed to find a recommended dose by achievement of the target concentration in plasma (50–100 ng/ml) and relationships with tumor shrinkage response and toxicity. They also measured serum VEGF and sVEGFR2 concentrations as potential biomarkers of drug response. A number of useful evidences on PK/PD (exposure–response) relationships were published for other tyrosine kinase inhibitors; e.g. efficacy of imatinib depended on plasma concentration of imatinib, and toxicity risk of erlotinib rose with increasing erlotinib AUC. The oncology community needs to pay more attention to PK/PD and clinical pharmacology for development and optimal use of molecular targeting drugs.

Simple methodology for the therapeutic drug monitoring of the tyrosine kinase inhibitors dasatinib and imatinib

A simple HPLC method has been developed to measure imatinib and N-desmethylimatinib (norimatinib) in plasma or serum at concentrations attained during therapy. Adaptation of this method to LC-MS/MS also allows dasatinib assay. A small sample volume (100 μL HPLC-UV, 50 μL LC-MS/MS) is required and analysis time is <5 min in each case. Detection was by UV (270 nm) or selective reaction monitoring (two transitions per analyte) tandem mass spectrometry. Assay calibration was linear (0.05-10 mg/L imatinib, 0.01-2.0 mg/L norimatinib and 1-200 µg/L dasatinib), with acceptable accuracy (86-114%) and precision (<14% RSD) for both methods. A comparison between whole blood and plasma confirmed that plasma is the preferred sample for imatinib and norimatinib assay. For dasatinib, although whole blood concentrations were slightly higher, plasma is still the preferred sample. Despite considerable variation in the (median, range) plasma imatinib and norimatinib concentrations in patient samples [1.66 (0.02-4.96) and 0.32 (0.01-0.99) mg/L, respectively, N = 104], plasma imatinib was >1 mg/L (suggested target for response) in all but one sample from patients achieving complete molecular response. As to dasatinib, the median (range) plasma dasatinib concentration was 13 (2-143) µg/L (N = 33). More observations are needed to properly assess the potential role of therapeutic drug monitoring in guiding treatment with dasatinib.