Abstracts

Levetiracetam (LEV) is a structurally novel AED that has a favorable PK profile including negligible protein binding and linear elimination kinetics. LEV does not appear to cause or be subject to significant PK interactions. LEV is highly water soluble, and is rapidly (Tmax~1 hr.) and extensively absorbed (F[gt]95%). Although previous studies have suggested that food does not impair the overall absorption of LEV, there is a lack of data regarding concomitant administration with enteral nutrition formulation (ENF). Given the utility of this agent, it is likely to be used in a variety of patient populations including children and the elderly. It may be speculated that alternative administration techniques such as crushing [amp] mixing with various semi-solid foods and/or ENF may be required. The objective of this study was to evaluate the oral absorption of LEV following concomitant administration with these vehicles.
This study used an unblinded, randomized, cross-over design. After an overnight fast, a single dose of 500mg LEV (Keppra) given as either as an [italic]intact[/italic] tablet with 120ml water (control, Phase I), or after being [italic]crushed and mixed[/italic] with 4 oz applesauce (Phase II), or 120ml ENF (Sustacal, Phase III). A 7 day washout period occured between each phase. Serial blood samples were obtained over 24 hrs in order to determine LEV serum concentration-time profile (GC NPD). Calculated pharmacokinetic variables included area under the concentration-time curve (AUC), max serum concentration (Cmax), and time to max serum concentration (Tmax) using non-compartmental methods.Statistical analysis was conducted with ANOVA.
N= 10 adult healthy volunteers (6 women/4 men)were evaluated (mean age and weight were 28.9 years and 78.6 kg, respectively). AUC values for phases I-III were 191.9[plusmn]50.2, 165.7.2[plusmn]43.4 and 168.3[plusmn]43.9 [mu]g*hr/ml, respectively, and did not significantly differ (p=0.38). Tmax did not significantly differ between any phase (1.08[plusmn]0.65, 1.32[plusmn]0.75 and 1.62[plusmn]0.73 hours, p=0.25). Cmax values for phase I-III were 14.8 [plusmn]5.6, 12.1[plusmn]2.8, and 10.8[plusmn]2.0 [mu]g/ml, respectively. While no significant differences were noted between control and any other study phase, there was a non-significant trend toward a lower Cmax (-27%, p=0.07) following co-administration with the ENF (Phase III). Mean LEV serum concentrations at 10 hrs post-dose however, were essentially the same for each study phase (Phase I-III: 3.9, 4.1, 4.0 [mu]g/ml, respectively). Long-term stability of LEV in these various formulations was not assessed.
These data suggest that the overall rate and extent of LEV oral absorption is not impaired following crushing [amp] mixing the tablet formulation with either a food vehicle or a typical ENF product. This method of LEV administration is therefore acceptable from a kinetic perspective. Our data do suggest slightly reduced peak serum concentrations following mixing with EF. The clinical significance of these modest changes is doubtful.
[Supported by: UCB-Pharma]