Abstracts

SPM 927 is in clinical development as a drug for treatment of epilepsy and neuropathic pain. The need may arise for a short-term intravenous (iv) replacement of an oral therapy with SPM 927 (eg. during surgery). This continuation of treatment could ideally be performed, if the iv formulation would be bioequivalent to the tablet. This trial was designed to investigate bioequivalence between 30 and 60 minutes (min) infusions of SPM 927 and the orally administered tablet. In a single-center, open-label, three-fold crossover trial 24 healthy male subjects (age: 31.8 [plusmn] 6.5 ys., weight: 74.7 [plusmn] 7.6 kg) received a single dose of 200 mg SPM 927 as 30-min infusion (Treatment A), as 60-min infusion (Treatment B) and orally as tablet (Treatment C). There was a wash-out phase of one week between each treatment. 18 blood samples per subject at each treatment were taken from predose until 72 hours after administration of SPM 927. SPM 927 plasma concentrations were detected with a LC-MS/MS method.
The following pharmacokinetic parameters were determined: AUC[sub]0-tz^,[/sub] AUC[sub]0-inf[/sub], C[sub]max[/sub], t[sub]max[/sub], t[sub][frac12][/sub], CL/f. Log transformed data of AUC[sub]0-tz[/sub], AUC[sub]0-inf[/sub], C[sub]max[/sub], and untransformed data of t[sub]max[/sub] were analyzed for each treatment using analysis of variance (ANOVA). Based on these analyses point estimates and 90% confidence intervals (90% CI) for the ratio[ldquo]30-min infusion / oral tablet[rdquo] and [ldquo]60-min infusion / oral tablet[rdquo] were calculated. Furthermore the differences for t[sub]max[/sub] between the treatments were calculated. All 24 subjects completed the 3 periods of the trial and were included in the analysis. C[sub]max[/sub] was 5.95[plusmn]1.49 [mu]g/mL, 5.38[plusmn]1.10 [mu]g/mL and 5.15[plusmn]1.40 [mu]g/mL, AUC[sub]0-tz[/sub] was 80.25[plusmn]16.64 h*[mu]g/mL, 81.18[plusmn]17.62 h*[mu]g/mL and 80.94[plusmn]17.52 h*[mu]g/mL, AUC[sub]0-inf[/sub] was 81.60[plusmn]18.04 h*[mu]g/mL, 82.38[plusmn]19.36 h*[mu]g/mL and 82.65[plusmn]18.88 h*[mu]g/mL, t[sub]max[/sub] was 0.7[plusmn]0.4 h, 1.2[plusmn]0.5 h and 1.2[plusmn]1.1 h, t[sub]1/2[/sub] was 11.9[plusmn]1.9 h, 12.0[plusmn]2.1 h and 12.1[plusmn]2.1 h and CL/f was 2.60[plusmn]0.78 L/h, 2.59[plusmn]0.81 L/h and 2.56[plusmn]0.72 L/h after the administration of SPM 927 as 30-minute infusion, 60-minute infusion and orally given drug, respectively.
The ratios [ldquo]30-min infusion / oral tablet[rdquo] (90% CI) for C[sub]max[/sub], AUC[sub]0-tz[/sub] and AUC[sub]0-inf[/sub] were 116% (109-123%), 99% (97-101%), and 99% (97-101%), respectively. The difference [ldquo]30-min infusion / oral tablet[rdquo] for t[sub]max[/sub] was -0.48h. The ratios [ldquo]60-min infusion / oral tablet[rdquo] (90% CI) for C[sub]max[/sub], AUC[sub]0-tz[/sub] and AUC[sub]0-inf[/sub] were 106% (99-113%), 100% (98-102%), and 100% (97-101%), respectively. The difference [ldquo]60-min infusion/ oral tablet[rdquo] for t[sub]max[/sub] was 0h. 90% confidence intervals of AUC[sub]0-tz[/sub], AUC[sub]0-inf[/sub] and C[sub]max[/sub] for ratios [ldquo]30-min infusion vs. oral tablet[rdquo] and [ldquo]60-min infusion vs. oral tablet[rdquo] were within the generally accepted bioequivalence range of 80-125%. Thus, bioequivalence to tablet was shown for both short-term infusions. Therefore, a short term replacement of an oral therapy with SPM 927 by an iv route is possible.