Bioequivalence of zonisamide orally dispersible tablet and immediate-release capsule formulations: results from two open-label, randomized-sequence, single-dose, two-period, two-treatment crossover studies in healthy male volunteers.
Author(s): Maanen R, Bentley D
Affiliation(s): Eisai Limited, Hatfield, United Kingdom. Rob_vanmaanenweisai.net
Publication date & source: 2009-06, Clin Ther., 31(6):1244-55.
Publication type: Research Support, Non-U.S. Gov't
BACKGROUND: To make it easier for patients who are prescribed zonisamide to administer their medicine, a rapidly disintegrating oral tablet formulation has been developed. OBJECTIVE: These 2 trials assessed the bioequiva-lence of a new orally dispersible tablet formulation of zonisamide (test) versus an immediate-release reference capsule. METHODS: Study 1 assessed the bioequivalence of a 100-mg orally dispersible tablet versus a 100-mg reference capsule. Study 2 assessed the bioequivalence of a 300-mg test tablet versus three 100-mg reference capsules. Both trials were open-label, randomized-sequence, single-dose, 2-period, 2-treatment crossover studies in consenting healthy male volunteers aged 18 to 55 years. A 4-week washout separated treatment periods. The zonisamide test tablet was placed on the tongue and, after it had dispersed in saliva, swallowed without water. Zonisamide serum concentrations were analyzed using a validated high-performance liquid chromatography assay with tandem mass spectrome-try detection (lower limit of quantification, 10 ng/nL). Bioequivalence was concluded if the 90% CI of the ratio of AUC(0-72) and C(max) were within the regulatory criteria of 0.80 to 1.25. The safety profile was assessed through adverse events (AEs) and analysis of laboratory and echocardiogram parameters. Results: In study one, 36 male subjects were enrolled and randomized (mean [SD] age, 26.1 [6.9] years; weight, 77.6 [11.0] kg; race: white, 35 [97.2%], and Asian, 1 [2.8%]). Of those, 7 were withdrawn prior to completion (5 were lost to follow-up, 1 failed the drug screening, 1 withdrew due to AEs, and 1 was excluded due to undisclosed medical history). In study two, 40 male subjects were enrolled and randomized (mean [SD] age, 31.2 [10.3] years; weight, 76.1 [9.0] kg; race: white, 38 [95.0%], black, 1 [2.5%], and other, 1 [2.5%]). Of those, 2 were withdrawn prior to completion (1 failed the urine drug screening and 1 withdrew consent). The ratios (90% CIs) of AUC(0-72) for the 100-mg and 300-mg test formulations were 1.00 (0.98-1.02) and 1.00 (0.98-1.01), respectively. The ratios (90% CIs) of C(max) were 0.97 (0.94-1.00) and 0.98 (0.95-1.00). A total of 25 subjects experienced treatment-emergent AEs in study 1; of these, 8 events in 3 patients were considered to be possibly or probably related to study drug administration. A total of 21 subjects experienced treatment-emergent AEs in study 2; of these, 11 events in 6 subjects were considered to be possibly or probably related to study drug administration. All AEs and laboratory and ECG findings were similar between formulations. CONCLUSIONS: The test formulation of zonisamide met regulatory criteria for bioequivalence to the reference formulation in these healthy male volunteers. Both formulations were generally well tolerated at both dose levels.
|