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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, CHARACTERISTICS
cyclosporine, erythromycin, itraconazole, ketoconazole, pimozide,grapefruit juice, and others. Enzyme inducers include barbiturates, Absorption
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 Metabolism
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
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