Imatinib blood level testing
Imatinib (Gleevec®/Glivec®, formerly STI571) has sparked a
CML is a clonal myeloproliferative disease characterized by the
revolution in cancer therapy by dramatically improving treatment
presence of the Philadelphia chromosome.1 This karyotypic
for Philadelphia chromosome–positive chronic myeloid leukemia
abnormality results from the reciprocal translocation of genetic
(Ph+ CML). Imatinib has produced unprecedented response rates
material between chromosomes 9 and 22, t(9;22), and leads to
that are durable for years in patients with Ph+ CML. More than 8
a fusion gene, the product of which is the constitutively active
years of experience with imatinib in clinical trials and 5 years in the
protein-tyrosine kinase, BCR-ABL. Biochemical signal transduction
post-approval setting have demonstrated that imatinib is not only
pathways stimulated by BCR-ABL kinase activity are responsible for
active but also is easy to administer, safe, and tolerable. We have
also learned that optimizing benefit with imatinib therapy involves
Imatinib is a small-molecule tyrosine kinase inhibitor that targets
ensuring that patients are taking the drug as prescribed by their
BCR-ABL.3,4 Inhibition of BCR-ABL kinase activity with imatinib
underlies its clinical efficacy. Imatinib is currently the standard of
This backgrounder provides information on the pharmacokinetics
care for all phases of Ph+ CML.5-10 In patients with Ph+ CML-chronic
of imatinib and the potential utility of blood level testing to optimize
phase (CP), response rates to imatinib are high and durable,
therapy with imatinib in the treatment of Ph+ CML. There are 4
whereas patients in advanced phases of Ph+ CML may experience
reasons why you may want to consider testing a patient’s imatinib
suboptimal responses and relapse more frequently.11 Various factors
have been shown to play a role in refractoriness to or relapse withimatinib therapy, including certain pharmacokinetic parameters of
■ You suspect that the patient may be nonadherent with imatinib.
imatinib that can affect drug exposure.12
■ You suspect that the patient may be experiencing a drug-drug
CLINICAL PHARMACOKINETICS OF IMATINIB
■ The patient is not responding to imatinib as well as you believe he
The pharmacokinetic parameters of imatinib have been
determined in patients with Ph+ CML from the phase 1 dose-findingstudy.13-15 Imatinib doses ranging from 25 mg to 1000 mg daily were
■ The patient is experiencing side effects that are unusually severe
tested. Imatinib exposure, as defined by the area under the curve
for the dose of imatinib he or she is taking.
(AUC) of plasma concentration of drug versus time after drugadministration, was found to be proportional to dose. A correlation was also observed with respect to imatinib dose andhematologic response in this trial.
Based on safety and efficacy results from the phase 3 InternationalRandomized Study of Interferon and STI571 (IRIS) trial, imatinib 400mg once daily is the recommended starting dose for patients withnewly diagnosed Ph+ CML-CP.9 Imatinib dose escalation isrecommended in cases of suboptimal response or loss ofresponse.16,17
Figure 1. Plasma concentration versus time profiles of Figure 2. Pharmacokinetic trough levels of drug at indicated imatinib in patients treated with imatinib 400 mg once daily18 imatinib doses in patients with Ph+ CML14,18,21,22
The lower and upper solid lines represent the pharmacokinetic profiles
Note: Top and bottom walls of each box represent 75th and 25th percentiles.
following the first dose on day 1 and at steady state.
Whiskers (error bars) above and below the box indicate the 90th and 10thpercentiles, and the dots represent 95th and 5th percentiles.
Drug exposure is usually described by plasma AUC. The troughplasma concentration at steady state (C
Table 1. Trough levels (C min) of drug in patients with Ph+ CML
measurement that is often used as the index for clinical monitoring
treated with imatinib at 400, 600, and 800 mg doses (800 mg
of drug exposure because it is easy to obtain and varies less with
dosed as 400 mg twice daily)
time. At the recommended imatinib starting dose of 400 mg/day,
the mean imatinib Cmin is approximately 1.0 µg/mL (Figure 1).18 At
imatinib doses of 600 mg/day and 800 mg/day (administered as 400
mg twice daily), the mean imatinib Cmins are approximately 1.4 and2.9 µg/mL, respectively. Administration of the 800 mg dose as 400
mg twice daily resulted in a higher Cmin compared with thatexpected from the 400 mg and 600 mg once daily doses (Figure 2).
Recent PK/PD analysis results showed that imatinib trough level
correlated with clinical response,19, 20 and it is recommended thatimatinib trough level should be maintained above 1.0 µg/mL for
clinical efficacy for patients with CML-CP.
SD, standard deviation; CV, coefficient of variance. SUMMARY OF IMATINIB PHARMACOKINETIC
Examples of CYP3A4 inhibitors include aprepitant, clarithromycin,
cyclosporine, erythromycin, itraconazole, ketoconazole, pimozide,grapefruit juice, and others. Enzyme inducers include barbiturates,
carbamazepine, dexamethasone, phenytoin, St. John’s wort,
Imatinib is freely soluble in water and, after oral
administration, is well absorbed from the gastrointestinal (GI)tract with a time to peak drug concentration of 1-3.3 hours. Elimination
Imatinib is 98% bioavailable. Absorption is the same between
The elimination half-life of imatinib is approximately 18 hours,
the tablet and capsule formulations and is not affected by
and thus it can be dosed once daily. The dose can be
food.14,23,24 Imatinib is absorbed primarily from the small intestine,
administered twice daily to minimize GI side effects or to
and the extent of absorption may be affected by the GI
maintain a low peak-to-trough concentration ratio for the high
anatomic abnormalities or disease states.25
imatinib doses. Steady state (no change with time) is reachedwithin a week. Distribution
Circulating imatinib is approximately 95% bound toplasma proteins, mainly albumin and alpha 1-acid glycoprotein
ADHERENCE WITH IMATINIB
(AAG). Plasma AAG levels have been shown to influenceimatinib pharmacokinetics in patients with CML.26 However,
With the advent of oral, targeted agents for cancer that are
AAG level may not affect the effective free-drug level because
prescribed for use as chronic therapy,30,31 the issue of adherence
this is determined by intrinsic clearance in patients. Individual
(compliance) to the prescribed regimen is emerging as a reason for
differences in AAG level and plasma protein binding may
concern by oncologists. One study showed that patients may
account for at least some of the interpatient variability
overestimate their adherence to oral cancer therapies by a factor of
in the observed total plasma exposure to imatinib. Imatinib is
2 in discussions with their physicians.31 Reasons for patients not
rapidly and extensively distributed into tissues, although with
taking their pills as prescribed include not fully understanding the
minimal penetration to the central nervous system.
importance of taking the medication as prescribed, experiencingunpleasant side effects, or simply forgetting to take the pills.30
For patients with life-threatening diseases, 95% adherence or
Imatinib is metabolized by cytochrome P450 (CYP) 3A4 and
greater is generally considered the goal.30
CYP3A5. Its major metabolite, N-desmethyl metabolite(CGR74588), has similar biologic activity to the parent drug
Recent studies have revealed that adherence for some patients with
Ph+ CML is suboptimal.32 A pharmacy record analysis of 4043patients prescribed imatinib indicated an average adherence rate of
Imatinib exposure has been shown to be influenced by drug-
78% over the 24-month study period for patients with Ph+ CML.
drug interactions with commonly prescribed drugs that
Patients were on therapy an average of 255 days over 24 months.
are either CYP3A4 inhibitors or inducers.27-29 In addition, drugs
Adherence to therapy began to decline after the first 4 months of
that are substrates of CYP2D6 and 2C19 may be affected by
imatinib. An updated list of drugs that are CYP3A4 inhibitors orinducers and CYP2D6 and 2C19 substrates canbe found on the internet at: http://medicine.iupui.edu/flockhart. Continued Figure 3. Imatinib adherence
While pharmacokinetic monitoring is widely used in many otherbranches of medicine, such as neurology, cardiology, and psychiatry,
it has not been widely applied, to date, in clinical oncology practice. However, monitoring of imatinib would most likely be beneficial to
physicians managing patients with Ph+ CML who demonstrate:
■ A less-than-expected response to imatinib
■ Side effects that are unusually severe for the dose of imatinib taken
Although imatinib is an easy drug to dose and administer,inadequate drug exposure due to pharmacokinetic factors or lack of
adherence to therapy may compromise clinical outcomes. Blood level
testing may offer a positive way for healthcare providers to initiate an
‘evidence-based’ discussion of the importance of adherence with
patients who are suspected of being non-adherent. Informationregarding imatinib blood exposure during therapy has the potential toserve as a valuable tool to guide clinical decision making in the era of
MONITORING OF PLASMA IMATINIB CONCENTRATIONS IN MANAGEMENT OF CML
Imatinib is the standard of care in CML. In the largest studyever performed in patients with newly diagnosed Ph+ CML-CP, 89%of patients randomized to imatinib are still alive with 5 yearsof trial follow-up.10 Achieving maximum benefit with imatinib therapymay require optimal dosing as well as adherence to therapy. Pharmacokinetic factors such as individual patient variation in drugabsorption and metabolism, interactions between prescribed medications,or other patient-related factors such as patients’ GI abnormalities ordisease conditions can also affect drug exposure and place maximumbenefit of therapy at risk.
The minimum effective concentration of imatinib has not been fullydefined, and the relationship between imatinib blood levels andoutcome remains a subject of investigation. Further studies are alsoneeded to characterize the safety/tolerability profiles of imatinib. Nevertheless, monitoring the drug levels in certain clinical situations asa first step to avoid low exposure would likely benefit patients.
Maintaining trough levels above the average concentration at the
intended clinical dose (1 µg/mL for 400 mg once daily dose), if
tolerable, is recommended. Imatinib blood levels below this average
concentration should be avoided and trigger further inquiry. References 1.
Goldman JM, Melo JV. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med. 2003;349:1451-1464.
Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5:172-183.
Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivoby a 2-phenylaminopyrimidine derivative. Cancer Res. 1996;56:100-104.
Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on thegrowth of Bcr-Abl positive cells. Nat Med. 1996;2:561-566.
Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate inchronic myelogenous leukemia. N Engl J Med. 2002;346:645-652.
Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses inpatients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002;99:3530-3539.
Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patientswith accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002;99:1928-1937.
Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfaplus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349:1423-1432.
O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newlydiagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004. 10. Druker BJ, Guilhot F, O'Brien SG, et al. for the IRIS investigators. Five-year follow-up of imatinib therapy for
newly diagnosed chronic myeloid leukemia in chronic-phase. N Engl J Med. 2006. In press. 11. Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome
resistance. Leukemia. 2004;18:1321-1331. 12. Deininger M. Resistance to imatinib: mechanisms and management. J Natl Compr Canc Netw. 2005;3:757-768. 13. Gschwind HP, Pfaar U, Waldmeier F, et al. Metabolism and disposition of imatinib mesylate in healthy
volunteers. Drug Metab Dispos. 2005;33:1503-1512. 14. Peng B, Hayes M, Resta D, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with
chronic myeloid leukemia patients. J Clin Oncol. 2004;22:935-942. 15. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase
in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037. 16. Gleevec® (imatinib mesylate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2006. 17. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia.
Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006. 18. Schmidli H, Peng B, Riviere GJ, et al. Population pharmacokinetics of imatinib mesylate in patients with
chronic-phase chronic myeloid leukaemia: results of a phase III study. Br J Clin Pharmacol. 2005;60:35-44. 19. Picard S, Titier K, Etienne G, et al. Trough plasma imatinib concentrations are associated with both
cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia [abstract]. Paperpresented at: American Society of Hematology, December 9-12, 2006; Orlando, Fla. Abstract 2141. 20. Larson RA, Druker BJ, Guilhot F, et al. on behalf of the IRIS Study Group. Correlation of pharmacokinetic data
with cytogenetic and molecular response in newly diagnosed patients with chronic myeloid leukemia inchronic phase (CML-CP) treated with imatinib—an analysis of IRIS study data [abstract]. Paper presented at:American Society of Hematology, December 9-12, 2006; Orlando, Fla. Abstract 429. 21. Blasdel C, Wang Y, Lagattuta T, Druker B, Letvak L, Egorin M. Therapeutic drug monitoring of imatinib and
impact on clinical decision making [abstract]. Paper presented at: American Society of Hematology; December9-13, 2006; Orlando, Fla. 22. Data on file. Novartis Pharmaceuticals. East Hanover, NJ, USA; 2005. 23. Nikolova Z, Peng B, Hubert M, et al. Bioequivalence, safety, and tolerability of imatinib tablets compared with
capsules. Cancer Chemother Pharmacol. 2004;53:433-438. 24. Peng B, Dutreix C, Mehring G, et al. Absolute bioavailability of imatinib (Glivec) orally versus intravenous
infusion. J Clin Pharmacol. 2004;44:158-162. 25. Beumer JH, Natale JJ, Lagattuta TF, Raptis A, Egorin MJ. Disposition of imatinib and its metabolite CGP74588 in
a patient with chronic myelogenous leukemia and short-bowel syndrome. Pharmacotherapy. 2006;26:903-907. 26. Gambacorti-Passerini C, Zucchetti M, Russo D, et al. Alpha1 acid glycoprotein binds to imatinib (STI571) and
substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res. 2003;9:625-632. 27. Dutreix C, Peng B, Mehring G, et al. Pharmacokinetic interaction between ketoconazole and imatinib mesylate
(Glivec) in healthy subjects. Cancer Chemother Pharmacol. 2004;54:290-294. 28. Bolton AE, Peng B, Hubert M, et al. Effect of rifampicin on the pharmacokinetics of imatinib mesylate
(Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol. 2004;53:102-106. 29. O'Brien SG, Meinhardt P, Bond E, et al. Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics
of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer. 2003;89:1855-1859. 30. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497. 31. Partridge AH, Avorn J, Wang PS, Winer EP. Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst. 2002;94:652-661. 32. Tsang J, Rudychev I, Pescatore SL. Prescription compliance and persistency in chronic myelogenous leukemia
(CML) and gastrointestinal stromal tumor (GIST) patients (pts) on imatinib (IM). J Clin Oncol. 2006;24:330s. Abstract 6119.
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