Abstracts

SPM 927 is a drug in clinical development for the treatment of epilepsy and neuropathic pain. Essential clinical pharmacological data have been established in a series of phase 1 trials. Clinical development in epilepsy requires information about possible drug-drug interactions between SPM 927 and other antiepileptic drugs (AEDs).
Two trials were designed to evaluate the influence of SPM 927 on valproic acid (VPA, trial SP601) and carbamazepine (CBZ, trial SP618) in 16 and 20 subjects, respectively. VPA was titrated up to 300mg bid over 17 days, CBZ up to 200mg bid over 22 days and SPM 927 up to 200mg bid over 7 (SP601) and 8 days (SP618).
Two additional trials were designed to evaluate the influence of VPA (trial SP602) and CBZ (trial SP603) in 16 and 20 subjects, respectively. 200mg bid SPM 927 was administered over 22 (SP602) or 17 (SP603) days, VPA was titrated up to 300mg bid over 13 days or CBZ up to 200mg bid over 8 days.
Each trial was an open label, randomized, multiple dose trial. Study participants were healthy male Caucasian subjects (18-45 years), all with normal body weight.
Steady state AUC (mcg[lowast]h/mL) and C[sub]max[/sub] (mcg/mL) of VPA were 433[plusmn]84 and 41[plusmn]7.9 for VPA alone and 449[plusmn]89 and 42[plusmn]8.6 for VPA together with SPM 927. The point estimates (combination of SPM 927+AED/sole treatment ratio) were 1.04 and 1.01, the 90% confidence intervals were 99-109 and 97-107%, respectively.
Steady state AUC (mcg[lowast]h/mL) and C[sub]max[/sub] (mcg/mL) of CBZ were 53[plusmn]8 and 4.7[plusmn]0.7 for CBZ alone and 57[plusmn]9 and 5.1[plusmn]0.8 for CBZ together with SPM 927. The point estimates were 1.07 and 1.09, the 90% confidence intervals were 104-111 and 104-114%, respectively.
Steady state AUC (mcg[lowast]h/mL) and C[sub]max[/sub] (mcg[lowast]h/mL) of SPM 927 were 83[plusmn]14 and 9.5[plusmn]1.3 for SPM 927 alone and 83[plusmn]14 and 9.7[plusmn]1.2 for SPM 927 together with VPA. The point estimates were 1.0 and 1.01, the 90% confidence intervals were 98-103 and 96-107%, respectively.
Steady state AUC (mcg[lowast]h/mL) and C[sub]max[/sub] (mcg/mL) of SPM 927 were 76[plusmn]17 and 8.5[plusmn]1.6 for SPM 927 alone and 82[plusmn]18 and 9.4[plusmn]2.2 for SPM 927 together with CBZ. The point estimates were 1.08 and 1.1, the 90% confidence intervals were 100-116 and 101-119%, respectively.
The elimination half-life (t[sub]1/2[/sub]) and T[sub]max[/sub] of SPM 927, VPA and CBZ remained unchanged after sole and combined treatment.
The 90% confidence intervals of the AUC and C[sub]max[/sub] point estimates were withhin the generally accepted bioequivalence ranges of 80-125%. SPM 927 had no influence on rate and extent of absorption of VPA or CBZ; VPA or CBZ did not influence the rate and extent of absorption of SPM 927. Thus, there is no indication for a drug-drug interaction between SPM 927 and VPA or CBZ. Pharmacokinetic data from longer-term studies of patients with epilepsy should be used to confirm the absence of interaction observed in these phase 1 trials.
[Supported by: Schwarz Biosciences GmbH, Alfred-Nobel-Strasse 10, D-40789, Monheim am Rhein, NRW, Germany]