Bioequivalence, safety, and tolerability of imatinib tablets compared with capsules.
ABSTRACT Imatinib (Glivec) has been established as a highly effective therapy for chronic myeloid leukemia and gastrointestinal tumors. The recommended daily dosage of 400-600 mg requires simultaneous intake of up to six of the current 100-mg capsules. Due to the need to swallow multiple capsules per dose, there is a potential negative impact on treatment adherence; therefore, a new imatinib 400-mg film-coated tablet has been developed. To improve dosing flexibility, particularly with regard to the pediatric population and the management of adverse events, a scored 100-mg film-coated tablet has also been introduced.
A group of 33 healthy subjects were randomly assigned to one of six treatment sequences, in which they received imatinib as 4 x 100-mg capsules (reference), 4 x 100-mg scored tablets (test), and 1 x 400-mg tablet (test). Blood sampling was performed for up to 96 h after dosing, followed by a 10-day washout period prior to the next sequence. After the third dosing, subjects were monitored to assess delayed drug-related adverse events. Pharmacokinetic parameters were assessed using concentration-time curves for plasma imatinib and its metabolite CGP74588.
Median Tmax was 2.5 h for capsules and tablets. Mean AUC((0-inf)) values were 27,094, 26,081 and 25,464 ng.h/ml for 4 x 100-mg capsules, 4 x 100-mg tablets, and 1 x 400-mg tablets, respectively. Cmax values were 1748, 1638 and 1606 ng/ml, and t(1/2) values were 15.8, 15.9 and 15.7 h. The test/reference ratios for AUC((0-inf)), AUC((0-96) (h)), and C(max) were 0.98, 0.98 and 0.95 for 4 x 100-mg tablets versus 4 x 100-mg capsules, and 0.95, 0.95 and 0.92 for 1 x 400-mg tablet versus 4 x 100-mg capsules. The 95% confidence intervals were fully contained within the interval (0.80, 1.25). Eight mild and one moderate adverse event considered to be drug related were reported. These events showed no clustering by type of dosage form and were of little to no clinical significance.
Film-coated 100-mg (scored) and 400-mg tablet dose forms of imatinib are bioequivalent to the commercial 100-mg hard-gelatin capsule, and are as safe and well tolerated.
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ABSTRACT: Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML. We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients). Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression. After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1 percent (95 percent confidence interval, 84.1 to 90.0) in the imatinib group and 34.7 percent (95 percent confidence interval, 29.3 to 40.0) in the group given interferon alfa plus cytarabine (P<0.001). The estimated rates of complete cytogenetic response were 76.2 percent (95 percent confidence interval, 72.5 to 79.9) and 14.5 percent (95 percent confidence interval, 10.5 to 18.5), respectively (P<0.001). At 18 months, the estimated rate of freedom from progression to accelerated-phase or blast-crisis CML was 96.7 percent in the imatinib group and 91.5 percent in the combination-therapy group (P<0.001). Imatinib was better tolerated than combination therapy. In terms of hematologic and cytogenetic responses, tolerability, and the likelihood of progression to accelerated-phase or blast-crisis CML, imatinib was superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML.New England Journal of Medicine 03/2003; 348(11):994-1004. · 51.66 Impact Factor
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ABSTRACT: The signal transduction inhibitor STI571 (formerly known as CGP 57148B) or Gleevec received fast track approval by the US Food and Drug Administration (FDA) for treatment of chronic myeloid leukemia (CML). STI571 is a revolutionary and promising new oral therapy for CML, which functions at the molecular level with high specificity. The dramatic improvement in efficacy compared to existing treatments prompted an equally profound increase in the pace of development of Gleevec. The duration from first dose in man to completion of the New Drug Application (NDA) filing was approximately 2.6 years. In order to support all pharmacokinetics studies with sufficient speed to meet various target dates, a semi-automated procedure using protein precipitation was developed and validated. A Tomtec Quadra 96 (Model 320) and a protein precipitation step in a 96-well plate format were utilized. A Sciex API 3000 triple quadrupole mass spectrometer with an atmospheric pressure chemical ionization interface operated in positive ion mode was used for detection. The method proved to be rugged and allowed the simultaneous quantification of STI571 and its main metabolite (CGP 74588) in human plasma. Herein, assay development, validation, and representative concentration-time profiles obtained from clinical studies are presented.Journal of Chromatography B 04/2002; 768(2):325-40. · 2.49 Impact Factor
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ABSTRACT: Constitutive activation of KIT receptor tyrosine kinase is critical in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate, a selective tyrosine kinase inhibitor, has been shown in preclinical models and preliminary clinical studies to have activity against such tumors. We conducted an open-label, randomized, multicenter trial to evaluate the activity of imatinib in patients with advanced gastrointestinal stromal tumor. We assessed antitumor response and the safety and tolerability of the drug. Pharmacokinetics were assessed in a subgroup of patients. A total of 147 patients were randomly assigned to receive 400 mg or 600 mg of imatinib daily. Overall, 79 patients (53.7 percent) had a partial response, 41 patients (27.9 percent) had stable disease, and for technical reasons, response could not be evaluated in 7 patients (4.8 percent). No patient had a complete response to the treatment. The median duration of response had not been reached after a median follow-up of 24 weeks after the onset of response. Early resistance to imatinib was noted in 20 patients (13.6 percent). Therapy was well tolerated, although mild-to-moderate edema, diarrhea, and fatigue were common. Gastrointestinal or intraabdominal hemorrhage occurred in approximately 5 percent of patients. There were no significant differences in toxic effects or response between the two doses. Imatinib was well absorbed, with pharmacokinetics similar to those reported in patients with chronic myeloid leukemia. Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor. Inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy.New England Journal of Medicine 09/2002; 347(7):472-80. · 51.66 Impact Factor