Bioequivalence, safety, and tolerability of imatinib tablets compared with capsules

Purpose: Imatimb (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. Experimental design: A group of 33 healthy subjects were randomly assigned to one of six treatment sequences, in which they received imatinib as 4x100-mg capsules (reference), 4x100-mg scored tablets (test), and 1x400-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. Results: Median T-max, was 2.5 h for capsules and tablets. Mean AUC((0-inf)) values were 27094, 26081 and 25464 ng.h/ml for 4x100-mg capsules, 4x100-mg tablets, and 1x400-mg tablets, respectively. C-max 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 4x100-mg tablets versus 4x100-mg capsules, and 0.95, 0.95 and 0.92 for 1x400-mg tablet versus 4x100-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. Conclusions: 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.