Abstracts

RATIONALE: SPM 927 is a functionalized amino acid that is being developed by Schwarz Biosciences GmbH as an oral and intravenous formulation for the treatment of epilepsy and neuropathic pain. Pharmacological potential has been shown in various preclinical in vitro and in vivo models. The clinical pharmacological properties of SPM 927 have been assessed in a series of Phase 1 studies in healthy subjects. The aim of this presentation is to describe the pharmacokinetics as well as the safety and tolerability profile of oral SPM 927.
METHODS: To evaluate basic pharmacokinetics, safety and tolerability of SPM 927, a dose-escalating single dose trial, a multiple dose trial and a food interaction trial were conducted. The investigations were performed in healthy male Caucasian subjects, aged between 18 and 45 years, with a normal body-weight. An approval by an IRB had been obtained, subjects gave written informed consent.
In the single dose trial 16 subjects received oral doses of 400, 600 and 800mg SPM 927 in a randomized, double-blind, placebo controlled design. The multiple dose trial (randomized, double-blind, placebo controlled, group comparison) was performed in 33 subjects who received 300 or 500mg SPM 927 bid over 14 days. The food effect was investigated in a randomized crossover design with 24 subjects who received single oral doses of 300mg SPM 927 with and without intake of a high fat meal.
RESULTS: Following 400, 600 and 800mg SPM 927 maximum plasma concentration (Cmax) was 8.7[plusminus]1.8, 14.3[plusminus]2.3 and 19.0[plusminus]4.8[mu]g/mL; area under the plasma concentration time curve (AUC) was 143[plusminus]27, 231[plusminus]49 and 302[plusminus]79[mu]g x h/mL; time to maximum concentration (tmax) ranged between 1 and 4 hours; terminal half-life (t1/2) was about 13 hours.
The multiple dose administration resulted in unchanged pharmacokinetic properties of SPM 927.
In the food effect trial equivalent pharmacokinetic parameters were found with and without intake of food: the 90% confidence intervals of the ratio [dsquote]fed/fasted[dsquote] for Cmax and AUC were 91-103% (point estimate 97%) and 97-100% (point estimate 98%), respectively.
SPM 927 was found to be safe in all three studies. There was no evidence for an influence on vital signs, ECG parameters or clinical laboratory values during treatment. Most frequent adverse events were CNS related symptoms like dizziness, paresthesia and fatigue. These symptoms were most pronounced after single doses of 800mg and multiple doses of 500mg bid. All 12 subjects in the 300mg bid group completed the trial according to protocol. Among 11 subjects randomized to 500mg bid, four completed the trial at this dose; the remaining seven experienced mild to moderate CNS-related adverse events that resulted in a dose-reduction to 400mg bid.
CONCLUSIONS: SPM 927 was rapidly absorbed, plasma concentrations were dose proportional. The elimination half-life of about 13 hours indicates that an od or bid treatment regimen may be possible. Pharmacokinetics after multiple dosing was not different from single dose administration. After bid treatment, steady state was reached within 2-3 days. There was no influence of concomitant food intake. The 90% confidence intervals for Cmax and AUC were within the bioequivalence acceptance range of 80 to 125%.
SPM 927 was safe and generally well tolerated following single doses of 400 to 600mg and multiple doses of 300 and 400mg bid .
[Supported by: Schwarz Biosciences GmbH
Alfred- Nobel-Str. 10 40789 Monheim am Rhein Germany]; (Disclosure: Salary - Schwarz Biosciences GmbH)