Single- and Multiple-Dose Bioequivalence and Food Effect Comparison Between Levetiracetam Extended Release Tablets Once Daily and Levetiracetam Immediate Release Tablets Twice Daily in Healthy Subjects
Abstract number :
3.233;
Submission category :
7. Antiepileptic Drugs
Year :
2007
Submission ID :
7979
Source :
www.aesnet.org
Presentation date :
11/30/2007 12:00:00 AM
Published date :
Nov 29, 2007, 06:00 AM
Authors :
E. Rouits1, I. Burton2, E. Guénolé3, M. Troenaru1, S. Bendahmane1, M. L. Sargentini-Maier1
Rationale: To compare the bioavailability of a new extended release levetiracetam 500 mg tablet (LEV XR) given once daily (OD) with that of levetiracetam 500 mg immediate release tablet (LEV IR; Keppra®) given twice daily (BID); to assess the effect of food on LEV XR. Methods: 24 healthy subjects (12M/12F) were randomised in this open-label, 3-way Latin square cross-over study. Under fasting conditions, 500 mg LEV IR BID or 2 x 500 mg LEV XR OD was administered on day 1 and from days 3 to 9. Plasma LEV concentration was determined serially on days 1 and 9. A single dose of 2 x 500 mg LEV XR was administered in the third treatment arm with a standard high-fat breakfast. Bioequivalence or lack of food effect was concluded if the 90% confidence intervals (CIs) of the pairwise adjusted geometric means ratios (XR/IR or fed/fasted) were entirely contained within 80-125% limits for Cmax, AUC(0-t) and AUC, and for Cmax and AUC(0-24) at steady-state.Results: Under fasting conditions, the time to peak was delayed by approximately 3 h with LEV XR (4 h vs. 0.9 h). CIs for comparisons of Cmax, AUC(0-t) and AUC ratios after single dosing were all within the bioequivalence limits. The steady-state AUC(0-24) ratios were also within the acceptance range. The average steady-state plasma concentration (Css,av)) was 12.9 µg/mL (13 CV%) and 13.6 µg/mL (16 CV%) for the XR and IR tablets, respectively. The time during which the LEV concentration remained ≥75% of Cmax was 7.8 h (27 CV%) vs. 3.4 h (67 CV%). The peak-to-trough fluctuation ratio (PTF) was 1.19 (12 CV%) vs. 1.27 (22%). When LEV XR was taken with a high-fat meal, the time to peak was delayed, but the Cmax) and AUC ratios remained within the bioequivalence limits. Drug-related adverse events (AEs), mostly of mild intensity, were reported by 13 (54%) and 17 (71%) subjects on LEV XR and LEV IR, respectively. The type and incidence of AEs following LEV XR did not differ from LEV’s known tolerability profile. All AEs resolved at the end of the study.Conclusions: The new LEV XR 500 mg tablet given OD is bioequivalent to the LEV IR tablet (Keppra®) given BID and its absorption is not modified by food intake. UCB funded
Antiepileptic Drugs