Abstract

INTRODUCTION

The greatest advancement in the therapy of chronic myeloid leukemia (CML) has been the introduction of imatinib mesylate (IM), a 2-phenylaminopyrimidine and selective inhibitor of BCR-ABL.[1] Imatinib produces durable responses, prolongs event-free and progression-free survival in patients with CML and is the current standard of care for this disease.[2,3] However, despite the high initial response rates, approximately 10-15% of early chronic phase patients will display primary or acquired cytogenetic resistance and even treatment failure to IM.[2,3] The key factors behind this are either biological factors such as BCR-ABL mutations or other genetic variations[4,5] and clinical features, such as the disease status or the high Sokal risk score.[1,2,3] More recently, it has been suggested that variations in plasma trough IM levels or other pharmacokinetic (PK)-related factors could also affect cytogenetic and molecular responses in CML.[6,7,8] This review attempts to present a brief summary of factors that affect imatinib PK and plasma levels, the plasma PK-response correlation and the current use of imatinib blood-level testing in various patient groups.

WHAT IS THE CURRENT IMPACT OF IMATINIB PLASMA LEVELS ON CLINICAL OUTCOMES?

Many studies have shown a correlation between imatinib trough plasma concentration and clinical response in various tumors.[6,7,8,9,10,11] In CML, four seminal studies have examined the relationship between trough plasma imatinib concentration and cytogenetic and molecular responses so far and have shown that mean trough plasma imatinib levels were significantly higher in patients with a complete cytogenetic response (CCR) or major molecular response (MMR) at the time of assessment than in those without at the same mean daily imatinib dose between the two groups.[6,7,8,9] One of these studies also showed that cumulative estimated CCR and MMR rates differed among the quartiles of imatinib trough levels (P =.01 for CCyR, P =.02 for MMR) and on multivariate analysis, imatinib trough concentration was found to be an independent predictor of the likelihood of CCR independently of Sokal risk group. There was a trend toward better event-free survival at 5 years in patients with higher trough imatinib concentrations. It was concluded that patients were more likely to achieve a satisfactory response to therapy if an adequate imatinib trough plasma concentration was achieved and maintained.[6] Most recently, the 1-year data from the phase III tyrosine kinase dose optimization study also confirm a correlation between IM trough plasma concentrations and clinical response.[8] Conversely, a recent small study of 78 CML patients failed to find any correlation between IM plasma concentration and response.[10] However, this study was limited by potential bias in the patient population, small patient numbers and heterogeneous sampling times.[10,11]

Correlation of imatinib plasma concentration with toxicity has not been consistently observed. In one study, a statistically significant correlation was observed between free drug exposure and toxicity in CML.[12] However, in the IRIS study, no correlation was observed except that higher imatinib concentrations were associated with greater risk of fluid retention, rash, myalgia or anemia, but less risk of fatigue, abdominal pain, joint pain or neutropenia. The authors suggested that the risk of some adverse effects may be influenced by disease burden or the speed of response to therapy. Discontinuations because of adverse events did not vary significantly among the quartiles.[6] Thus, the role of imatinib plasma concentrations in predicting toxicity remains to be confirmed.

HOW VARIABLE IS IMATINIB PLASMA EXPOSURE?

IM has a good PK profile with rapid oral absorption uninfluenced by food, almost-complete bioavailability, a proportionate dose-response relationship and a terminal elimination half-life (˜18 h) compatible with once-daily dosing.[13,14] Steady-state plasma concentration is achieved after 5-7 days of therapy.[13] Although, intrapatient variability in imatinib trough blood concentrations is small, but the interpatient variability in exposure to imatinib at the same dose can be substantial with a coefficient of variation of 40-60%.[6,7,13] Data from the phase III IRIS study reported by Larson et al. also showed high interpatient variability in plasma imatinib concentrations. Trough plasma imatinib was measured at steady state before morning dosing on day 29 in 351 patients receiving 400 mg/day. The overall mean Cmin was 979 ± 530 ng/ml, with a coefficient of variation of 54.1%. CGP74588, the active N-desmethyl metabolite of imatinib, had a similar coefficient of variation for trough concentrations (43.6%).[6] Large interpatient variability of IM trough levels concentrations ranging from 181 to 2947 ng/ml was also noted in a French study in patients with CML receiving IM at 400 or 600 mg/day.[7]

WHAT ARE THE POTENTIAL REASONS FOR VARIATIONS IN IMATINIB PLASMA CONCENTRATIONS?

There are many potential reasons; first is poor compliance due need for prolonged life-long therapy. In general, 95% adherence is generally considered the goal for patients with life-threatening diseases.[15] In a recent analysis, only 41% of patients had good compliance, which continued to decrease with time.[15] Secondly, many demographic factors including sex, age, body weight and BSA, have been shown to have mild impact on imatinib exposure.[6,16] Third, imatinib is metabolized by the cytochrome P450 (Cyp), mainly through its CYP3A4 isoform.[17] Interpatient or interracial variability in CYP3A4 activity may lead to variable imatinib exposure among patients.[18] Furthermore, CYP3A4 activity can be affected by drug-drug interactions due to simultaneous use of other drugs, which are either cytochrome enzyme inhibitors or inducers.[16] Finally, imatinib levels may be altered by the gastrointestinal tract diseases or anatomic abnormalities due to poor absorption and differences in plasma protein binding of IM.[19,20]

HOW TO MEASURE TROUGH PLASMA CONCENTRATIONS?

Imatinib exposure may be monitored by measuring the area under the curve of plasma concentration versus time and peak concentrations or trough concentration estimation. Of these, trough plasma concentrations of imatinib are easily estimable and are most widely assayed. Trough concentration blood samples are collected before morning dosing at steady state and are typically determined using rapid, simple, sensitive and specific liquid chromatography–mass spectrometry (LC-MS) or high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometry protocols which have been validated very well.[6,7,21,22] Alternatively, HPLC coupled with ultraviolet (UV) diode array detection can also be used to quantify imatinib. However, this method needs to be further validated as per the current Food and Drug Administration guidelines. Novel tools such as measurement of intracellular imatinib concentrations or activity of cellular uptake/efflux transporters such as multidrug resistance protein 1 (also known as P-glycoprotein), multixenobiotic resistance protein (also known as breast-cancer resistance protein) and human organic cation transporter 1 are being used primarily for research purposes and these tests are not widely available.[23,24,25,26]

WHAT IS THE THERAPEUTIC CONCENTRATION WINDOW FOR IMATINIB?

This has not been clearly defined. In the two seminal studies, plasma imatinib concentrations of more than 1002 ng/ml and more than 1009 ng/ml were significantly associated with the achievement of good cytogenetic and molecular responses. Hence, it is suggested that ensuring plasma trough concentrations at or above the mean population concentration of 1000 ng/ml could be critical for achieving superior rates of CCR and MMR.[6,7] However, it would be imperative to study the clinical impact of maintaining imatinib concentrations over a sustained period since the importance of factors such as intrapatient variability over time, interactions with other medications and the effect of dose changes and treatment interruptions has not been fully investigated.

WHEN TO MEASURE THE LEVELS?

Therapeutic drug monitoring (TDM) could be of value in many clinical situations: First, when patients have a suboptimal response or treatment failure, measurement of trough plasma imatinib concentration could further assist the clinician in deciding whether to escalate the dose in addition to other important factors influencing decision making.[27] Second, when patients develop unusually severe adverse reactions and have supratherapeutic levels, a dose reduction may help as shown in recent small reports.[28] Third, when the clinician suspects a drug-drug interaction because of concomitant use of a cytochrome inducer or inhibitor or drug with unknown interaction with imatinib and measurement shows low imatinib concentration, imatinib dose should be increased or suspect drug stopped and replaced with a safer drug. A repeat level after the intervention should be done to ensure the “therapeutic” concentration of imatinib. Finally, in case of a poor level prompted by suboptimal response, drug compliance should be checked. Compliance monitoring can be done through random unscheduled measurement of trough plasma concentration. Although, measurement of plasma concentrations may assist in these difficult cases, decisions regarding the need for treatment interruption, dose reduction or change of therapy should always be based on the overall clinical situation until further data is available.

WHAT ARE THE PITFALLS OF MEASURING THE LEVELS?

Measuring trough plasma concentrations provides an additional tool for the management of patients taking imatinib especially if a patient fails to achieve a satisfactory response in accordance with published recommendations or has severe or unusual toxicity. Since there is no data on the impact of changes in therapeutic strategy based on trough plasma concentrations, it cannot be considered a standard therapeutic tool. As there are multiple factors in addition to plasma exposure that affect response, the therapeutic threshold of 1000 ng/ml is currently accepted as a population mean value associated with clinical response and not the target concentration for a specific patient. Furthermore, there is still limited data on the value of longitudinal measurement of trough plasma concentrations, the concentrations attained in patients receiving higher doses (>400 mg) or twice daily schedule and changes in plasma concentrations after alterations in dose. A prospective clinical trial examining the impact of dose increases in patients with low plasma levels, is in progress (monitoring imatinib) and would, hopefully, be able to address these issues.[29] Thus, whenever measured, plasma concentrations should be interpreted and decisions made in the context of all the clinical information available.

WHAT ARE THE IMATINIB LEVELS IN INDIAN POPULATION?

CONCLUSIONS

Plasma levels of imatinib vary significantly among patients due to variable compliance, CYP enzyme polymorphism, demographic factors and drug interactions.[6,15,16,17,18,19,20] The therapeutic plasma trough imatinib concentration in CML has been considered to be 1000 ng/ml or above.[6,7] Measurement of plasma levels may be useful in patients with suboptimal response, suspected drug interaction, unusual or severe toxicity and suspect non-compliance. However, clinical parameters should guide medical management of most patients since there is variability in the test and it has not been prospectively validated. There is a need to study the role of doing minimal trough imatinib concentrations sequentially, impact of dose modification based on trough levels and impact of demographic or clinical factors such as advanced disease, higher Sokal risk scores and BCR-ABL mutations. The recently completed “The Imatinib Concentration Monitoring Evaluation study” would probably be able to answer these questions.[31] In future, TDM may become an important therapeutic tool for management of patients with CML with this added information.

ACKNOWLEDGMENTS

Footnotes