Imatinib

Pharmacokinetics

The mean absolute systemic availability of imatinib is about 98% [ ]. CYP3A4 plays a pivotal role in imatinib metabolism; N-demethylated imatinib is the main metabolite and is active [ ]. The plasma AUC for this metabolite is about 15% of the AUC of imatinib. Drug elimination is primarily mediated via the feces [ , ]. The half-lives of imatinib and N-demethylimatinib are 18–27 hours and 40–74 hours respectively. The peak concentrations average 3340 ng/ml and 781 ng/ml, and trough concentrations 1540 ng/ml and 508 ng/ml respectively [ ]. These values were not changed significantly in patients with end-stage renal disease or on hemodialysis. Dosage adjustment is not therefore necessary in patients with renal impairment [ ]. Imatinib can also be used in patients with even severely impaired hepatic function [ ].

Adverse effects and adverse reactions

Imatinib is generally well tolerated. Besides mild to moderate hematological toxicity, adverse reactions include fluid retention, edema, nausea, and some skin disorders [ , ]. There have also been reports of hepatitis.

Cardiovascular

It has been suggested that imatinib may have caused severe heart failure and left ventricular dysfunction in 10 patients with pre-existing conditions such as hypertension, diabetes mellitus, and coronary heart disease [ ]. Experimental studies have shown that imatinib induces apoptosis in isolated cardiac myocytes [ ]. Several trials and a database of six registration trials have therefore been reviewed.

• The Italian Cooperative Study Group—four consecutive studies of imatinib therapy in 833 patients with Philadelphia chromosome-positive chronic myeloid leukemia, observed for a median of 19–64 months [ ]. The overall cardiac mortality rate was 0.3%.

• The MD Anderson experience—clinical trials of imatinib from July 1998 to July 2006, with median follow-up of 5 years [ ]. In all the imatinib protocols, standard research monitoring procedures were conducted before treatment and at regular intervals. Electrocardiography, echocardiography, and chest radiography were conducted routinely before treatment and as clinically indicated during follow-up. The eligibility criteria excluded patients with cardiac problems (NYHA classes III and IV). After reviewing all reported adverse events, particularly those that could be considered as having a cardiac origin, 22 patients (1.8%) were identified as having symptoms that could be attributed to congestive heart failure, of whom 12 had previously received interferon and three had received anthracyclines. They included nine patients reported elsewhere [ ]. Their median age was 70 (range 49–83) years. The median time from the start of imatinib therapy to a cardiac adverse event was 162 (range 2–2045) days. Eighteen patients had previous medical conditions that predisposed them to cardiac disease: congestive heart failure (n = 6), diabetes mellitus (n = 6), hypertension (n = 10), coronary artery disease (n = 8), dysrhythmias (n = 3), and cardiomyopathy (n = 1). Of the 22 patients, 15 underwent echocardiography or multiple gated acquisition (MUGA) scanning at the time of the event: nine of these 15 patients had low ejection fractions, and six of these nine had significant conditions that predisposed them to cardiac disease (three had coronary artery disease, two congestive heart failure, and one a cardiomyopathy). Of the 22 patients with symptoms of congestive heart failure, 11 continued to take imatinib with dosage adjustments and management of congestive heart failure without further complications. However, with the host of confounding factors involved in these patients, the occurrence of congestive heart failure related to the use of imatinib was reasonably unambiguous in only seven of the 1276 patients reviewed (0.5%).

• Novartis clinical database—six registration trials comprising 2327 patients who took imatinib as monotherapy. These trials represented 5595 patient-years of exposure to imatinib (average exposure 2.4 years). Twelve cases of congestive heart failure (0.5%) were considered to be incident cases (with no previous history of congestive heart failure or left ventricular dysfunction) with a possible or probable relation to imatinib. If these cases are related to the 5595 patients-years of imatinib exposure the incidence of congestive heart failure is 0.2% per year across all trials.

• In an international, randomized phase III study, 1106 patients with newly diagnosed chronic myeloid leukemia were randomized to either initial therapy with imatinib or the previous standard treatment of interferon + cytosine arabinoside [ ]. Both regimens were examined for cardiac safety according to an analysis of adverse events as described above. The incident cases of cardiac failure and left ventricular dysfunction, possibly or probably related to exposure to the study medication, was 0.04% per year (1 case in 2309 patient-years) for patients taking imatinib versus 0.75% per year (four cases in 536 patient-years of exposure) in patients taking interferon + cytosine arabinoside.

Congestive heart failure attributable to imatinib seems to be rare. When it occurs, the symptoms most commonly occur in elderly patients with pre-existing cardiac conditions and may often reflect predisposing cardiac compromise compounded by some element of fluid retention. Patients with a previous cardiac history should be monitored closely and treated aggressively with diuretics if they develop fluid retention.