Abstracts

SPM 927, a functionalized amino acid, is currently being developed by Schwarz Biosciences GmbH as a drug for treatment of epilepsy and neuropathic pain. Safety and tolerability of SPM 927 have been investigated in preclinical and clinical trials. As with most new chemical entities the potential for cardiovascular effects of SPM 927 in patients with epilepsy should be fully explored. The objective of this trial was to evaluate the relationship between the administration of adjunctiveSPM 927 and changes in the QTc- and PR-interval of patients with partial seizures.
This investigation was a retrospective analysis of pharmacokinetic and ECG data collected for trial SP607, an open label, dose titration trial to determine tolerability and efficacy of oral SPM 927 as adjunctive therapy in patients with partial seizures with or without secondary generalization (n=91). During the 6 week dose escalation phase, SPM 927 was increased from 100mg/day up to a maximum of 600mg/day or to the maximum tolerated dose in weekly steps of 100mg/day. A 4 week maintenance phase followed. Blood samples for the pharmacokinetic assessments were taken weekly to analyze SPM 927. Analysis of SPM 927 in plasma samples was performed using a validated LC-MS/MS method. The lower limit of quantification was 0.1mcg/mL and the calibration range was 0.1-20mcg/mL.
Close to time of blood sampling (2-4hrs after SPM 927 dose, [sim]Tmax), an ECG was recorded and PR and QTc (heart rate corrected by Bazett, Fridericia and Framingham) were determined automatically.
PR and QTc intervals were plotted vs SPM 927 plasma concentrations. Correlation was tested by SAS procedure REG using the model [quot]parameter=intercept+slope[lowast]concentration[quot].
The mean point estimate of SPM 927 plasma concentrations after administration of 600mg/day of SPM 927 was 11.9[plusmn]5.6mcg/mL. None of the ECG parameters showed a correlation with the SPM 927 plasma concentrations. A PR-interval increase of less than 10msec and an unchanged QTc can be derived from the slope of the equations describing the correlation of ECG parameters with SPM 927 plasma concentrations. PR-interval was estimated using SPM 927 plasma concentrations by means of the equation PR (msec) = 163.4msec+0.191*SPM 927msec. The individual difference of PR to baseline was described by delta PR (msec) = -1.723msec+0.886[lowast]SPM 927msec. Corresponding equations for QTc (Bazett) and delta QTc were QTc (msec) = 417.2msec-0.035[lowast]SPM 927msec and delta QTc = 0.116msec-0.036[lowast]SPM 927msec.
Within the dose levels up to 600mg/day SPM 927 did not have a clinically important influence on electronical conductivity (PR) and the repolarization (QTc) of the myocardium. These results correspond to those found in healthy subjects. Controlled clinical trials in patients with epilepsy are ongoing to confirm these preliminary findings.
[Supported by: Schwarz Biosciences GmbH, Alfred-Nobel-Strasse 10, D-40789 Monheim am Rhein, NRW, Germany]