Abstract
Purpose
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.
Experimental design
A group of 33 healthy subjects were randomly assigned to one of six treatment sequences, in which they received imatinib as 4×100-mg capsules (reference), 4×100-mg scored tablets (test), and 1×400-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.
Results
Median Tmax was 2.5 h for capsules and tablets. Mean AUC(0–inf) values were 27094, 26081 and 25464 ng·h/ml for 4×100-mg capsules, 4×100-mg tablets, and 1×400-mg tablets, respectively. Cmax values were 1748, 1638 and 1606 ng/ml, and t1/2 values were 15.8, 15.9 and 15.7 h. The test/reference ratios for AUC(0–inf), AUC(0–96 h), and Cmax were 0.98, 0.98 and 0.95 for 4×100-mg tablets versus 4×100-mg capsules, and 0.95, 0.95 and 0.92 for 1×400-mg tablet versus 4×100-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.
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.
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Acknowledgements
We wish to thank members of the nursing and research staff who participated in this study. The support of Petra Brinkmann, Ann E. Bolton, Agnes Brunner, and Roland Waite at Novartis is gratefully acknowledged. All experimental procedures performed in this study were in accordance with current Swiss law.
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Nikolova, Z., Peng, B., Hubert, M. et al. Bioequivalence, safety, and tolerability of imatinib tablets compared with capsules. Cancer Chemother Pharmacol 53, 433–438 (2004). https://doi.org/10.1007/s00280-003-0756-z
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DOI: https://doi.org/10.1007/s00280-003-0756-z