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Bioavailability of three rufinamide oral suspensions compared with the marketed 400-mg tablet formulation: results from a randomized-sequence, open-label, four-period, four-sequence crossover study in healthy subjects.

Abstract：

BACKGROUND:Rufinamide is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients aged ≥4 years. OBJECTIVES:The primary purpose of this study was to compare the relative bioavailability and other pharmacokinetics of rufinamide administered as a 400-mg tablet formulation (reference) with 10 mL of a newly developed 40-mg/mL suspension (test) manufactured using 3 different homogenization speeds in healthy subjects under fed conditions. The study also explored whether homogenization speed had any effect on rufinamide pharmacokinetics when administered as a suspension formulation. METHODS:This was a randomized, open-label, crossover, single-dose study in healthy, fed subjects aged 18 to 55 years (inclusive), conducted at a single center in the United Kingdom. Subjects were randomized to 1 of 4 treatment sequences, with each sequence consisting of 4 treatment periods. In each treatment period, subjects received a single dose of either the reference product (400-mg rufinamide tablet) or the test product (10 mL of rufinamide suspension [40 mg/mL] manufactured using 3 different homogenization speeds [1800, 2100, and 3000 revolutions per minute (rpm)]). Serial blood samples were collected for 72 hours after dosing for the measurement of rufinamide in plasma. Primary comparisons between test (suspension) and reference (tablet) formulations focused on AUC from 0 to 72 hours (AUC(0-72 h)) and C(max). The formulations were considered bioequivalent if the ratios of geometric least squares means and associated 90% CIs of AUC(0-72 h) and C(max) were within the predetermined range of 80%-125%, according to the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) requirements. Tolerability was assessed by subject interviews, physical examinations, and laboratory tests. RESULTS:Twenty-four healthy subjects were randomized: 8 were male and 16 were female; 22 white, 1 black, and 1 Asian subjects were enrolled. Mean (SD) age was 29.8 (10.0) years. Mean weight was 68.2 (11.0) kg, and mean body mass index was 23.6 (3.0) kg/m(2). Twenty-one subjects completed the study; 2 subjects discontinued because of adverse events (both urinary tract infections considered unrelated to treatment) and 1 because of protocol deviation. The 72-hour pharmacokinetic data for the last complete treatment period before discontinuation were included in group means. The geometric least squares mean C(max) value for the reference tablet formulation was 4840.24 ng/mL; and 4254.87, 4204.29, and 4418.44 ng/mL for the 1800-, 2100-, and 3000-rpm test suspensions, respectively. The ratios of the geometric least squares mean values (test/reference) for C(max) were 0.88 (90% CI, 0.84-0.92), 0.87 (0.83-0.91) and 0.91 (0.88-0.95) for the 1800-, 2100-, and 3000-rpm suspensions, respectively, compared with the tablet formulation. The geometric least squares mean AUC(0-72 h) values were 75,960.48 ng · h/mL for the tablet formulation and 74,279.02, 73,746.03, and 73,701.17 ng · h/mL for the 1800-, 2100-, and 3000-rpm suspensions, respectively. The ratios of the geometric least squares mean values (test/reference) for AUC(0-72 h) were 0.98 (90% CI, 0.95-1.00), 0.97 (0.95-1.00) and 0.97 (0.95-0.99) for the 1800-, 2100-, and 3000-rpm suspensions, respectively, compared with the tablet formulation. The ratios and associated 90% CI limits (for test suspensions to the reference tablet) for AUC(0-72 h) and C(max) were within the FDA and EMA criteria for assuming bioequivalence to the 400 mg tablet. Comparisons among the 3 rufinamide test suspensions also met the regulatory criteria for assuming bioequivalence to one another. Treatment-emergent adverse events (TEAEs) were experienced by 18.2% (4/22) of subjects treated with the 400-mg tablet, 21.7% (5/23) of subjects treated with the 1800-rpm suspension, 26.1% (6/23) of subjects treated with the 2100-rpm suspension, and 8.7% (2/23) of subjects treated with the 3000-rpm suspension. Overall, 54.2% (13/24) of subjects experienced a TEAE; all TEAEs were mild or moderate in severity, with headache being the most frequently reported (37.5% [9/24]). There were no serious adverse events or deaths. CONCLUSION:This single-dose study in a small population of fed, healthy subjects found no statistically significant differences in relative bioavailability among each of the 3 test suspensions and the currently marketed 400-mg tablet formulation of rufinamide, meeting FDA and EMA regulatory requirements for assuming bioequivalence.

journal_name

Clin Ther

journal_title

Clinical therapeutics

authors

Critchley DJ,Aluri J,Boyd P,Whayman M,Narurkar M,Delargy H,Bibbiani F

doi

10.1016/j.clinthera.2011.01.016

subject

Has Abstract

pub_date

2011-01-01 00:00:00

pages

146-57

issue

1

eissn

0149-2918

issn

1879-114X

pii

S0149-2918(11)00017-8

journal_volume

33

pub_type

杂志文章,随机对照试验

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