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

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• 作者：David John Critchley PhD¹ ; ^{david_critchley@eisai.net} ; Jagadeesh Aluri MS² ; Peter Boyd MSc¹ ; Matthew Whayman MSc¹ ; Milind Narurkar PhD² ; Hugh Delargy PhD¹ ; Francesco Bibbiani MD²
• 关键词：bioavailability ; bioequivalence ; oral ; rufinamide ; suspension ; tablet
• 刊名：Clinical Therapeutics
• 出版年：2011
• 出版时间：January 2011
• 年：2011
• 卷：33
• 期：1
• 页码：146-157
• 全文大小：356 K

文摘

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_0–72h) and C_max. The formulations were considered bioequivalent if the ratios of geometric least squares means and associated 90 % CIs of AUC_0–72h 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/m². 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_0–72h 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_0–72h 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_0–72h 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.