Abstracts

SPM 927 is a new drug developed for the treatment of epilepsy and neuropathic pain. Essential clinical pharmacologic data have been established in a series of phase 1 trials. Clinical development requires information about a possible influence of concomitant food intake on the pharmacokinetics of SPM 927. In a single-center, open-label, two-fold crossover trial 24 healthy male subjects (age: 30.5 [plusmn] 6.5 ys., weight: 74.7 [plusmn] 7.9 kg) received a single oral dose of 300 mg SPM 927 in the fasted state (treatment A) and 30 minutes after a standard high-fat and high-calorie breakfast (treatment B) in accordance with the FDA guidelines. There was a wash-out phase of one week between the two periods. In each period, 15 blood samples were taken from predose until 72 hours after administration of SPM 927. SPM 927 plasma concentrations were detected with a highly sensitive and selective LC-MS/MS method. The following pharmacokinetic parameters were determined using non-compartmental methods: maximum plasma concentration (C[sub]max[/sub]), area under the concentration time curve from zero up to the last measurable plasma concentration (AUC[sub]0-tz[/sub]) and up to infinity (AUC[sub]0-inf[/sub]), time to reach C[sub]max[/sub] (t[sub]max[/sub]), terminal half-life (t[sub][frac12][/sub]). Log transformed data of C[sub]max[/sub], AUC[sub]0-tz[/sub], AUC[sub]0-inf[/sub] and untransformed data of t[sub]max[/sub] in the fasted and fed state were analyzed using analysis of variance (ANOVA). Based on these analyses point estimates and 90% confidence intervals (CI) for the ratio (for C[sub]max[/sub], AUC[sub]0-tz[/sub] and AUC[sub]0-inf[/sub]) [ldquo]fed[rdquo] versus [ldquo]fasted[rdquo] and for the difference (t[sub]max[/sub]) [ldquo]fed[ldquo] minus [ldquo]fasted[ldquo] were calculated. All 24 subjects completed both periods of the trial and were included in the analysis. C[sub]max[/sub] was 7.4 [16.9] [mu]g/mL (geom. mean [geom. CV%]) and 7.7 [15.3] [mu]g/mL, AUC[sub]0-tz[/sub] was 138.0 [13.2] h*[mu]g/mL and 140.8 [13.1] h*[mu]g/mL, AUC[sub]0-inf[/sub] was 141.9 [13.5] h*[mu]g/mL and 144.3 [13.3] h*[mu]g/mL after the administration of 300mg SPM 927 under [ldquo]fed[rdquo] and [ldquo]fasted[rdquo] conditions, respectively. t[sub]max[/sub] under [ldquo]fed[rdquo] as well as under [ldquo]fasted[rdquo] conditions was between 0.5 h and 4.0 h. Geom. mean of t[sub][frac12][/sub] was nearly identical with 13.4 h and 13.3 h under [ldquo]fed[rdquo] and [ldquo]fasted[rdquo] conditions, respectively.
The ratios [ldquo]fed[rdquo] versus [ldquo]fasted[rdquo] (90% CI) for C[sub]max[/sub], AUC[sub]0-tz[/sub] and AUC[sub]0-inf[/sub] were 97% (91-103%), 98% (96-100%), and 98% (97-100%), respectively. The difference [ldquo]fed[rdquo] minus [ldquo]fasted[rdquo] (90% CI) for t[sub]max[/sub] was 0.5h (0.0-1.0h]. The 90% confidence intervals of the AUC[sub]0-tz[/sub], AUC[sub]0-inf[/sub] and C[sub]max[/sub] point estimates were within the generally accepted bioequivalence ranges of 80-125%. Thus, it was demonstrated that administration with food does not alter the rate or extent of gastrointestinal absorption of SPM 927. Based on these results, it can be concluded that SPM 927 can be taken without regard to meals. (Supported by Schwarz Biosciences GmbH, Alfred-Nobel-Stra[szlig]e 10, 40789 Monheim, Germany)