Abstracts

RATIONALE: Autoinduction is an important consideration in epilepsy treatment and is a characteristic of numerous antiepileptic drugs (AEDs) including carbamazepine (CBZ), phenytoin, phenobarbitone, valproate and lamotrigine. Autoinduction by CBZ can be considered by far the most important clinically. AEDs that are not autoinducers are preferred because they exhibit linear kinetics and consequently make treatment strategies simpler. This study was designed to determine and compare the blood and cerebrospinal fluid (CSF) kinetics of CBZ and the new AED lrevetiracetam (LEV) during 7 consecutive days of continuous administration to freely behaving rats.
METHODS: Under halothane anaesthesia, male Sprague Dawley rats (300-350 g) had a catheter placed in the internal jugular vein for blood sampling, a cannula in the cisterna magna for CSF sampling and an osmotic minipump in the peritoneal cavity. Minipumps were set to deliver CBZ (2 and 4 mg/kg/hr) or LEV (8 and 16 mg/kg/hr) at 48 hours after surgery and continue drug delivery for seven consecutive days thereafter. Blood and CSF samples were collected at 30 min intervals for 6-9 hrs on days 1, 2, 4, 6 and 7. Samples were analysed for CBZ, carbamazepine-epoxide (CBZ-E) and LEV content using high performance liquid chromatography.
RESULTS: CBZ was rapidly absorbed from the peritoneal cavity with peak concentrations in blood and CSF occurring 4 hrs and 6 hrs later, respectively. Peak blood CBZ-E concentrations occurred at 24 hrs whilst for CSF it was 9 hrs. Both CBZ and CBZ-E exhibited dose-proportionality. On day 2 CBZ concentrations declined substantially and significantly (by 50-75%) and continued to decline during the subsequent 5 days. CBZ-E concentrations showed a precipitous decline on day 4. Like CBZ, LEV was also rapidly absorbed from the peritoneal cavity with peak blood and CSF concentrations occurring by 9 hrs and concentrations were dose-dependent. However, in contrast to CBZ, steady-state LEV concentrations showed no evidence of decline during the subsequent 6 days of LEV administration.
CONCLUSIONS: The significant decline in blood and CSF concentrations of CBZ and CBZ-E by the second day of CBZ administration is an indication of the potent autoinduction characteristics of CBZ. In contrast steady-state blood and CSF LEV concentrations did not change during 7-days of continuous LEV administration suggesting that LEV is not associated with autoinduction.
[Supported by: National Society for Epilepsy]; (Disclosure: Honoraria - UCB Pharma)