Buccal and rectal pharamacokinetics of diazepam for treatment of seizures in children

Abstract

To examine the pharmacokinetics of diazepam administered via buccal route and feasibility of buccal administration to be an alternative to rectal administration for treatment of seizure in children by compared the pharmacokinetic parameters after buccal and rectal administrations. The opened-label, randomized, 2-way crossover trial was carried in twenty epileptic children at Queen Sirikit National Institute of Child Health. Twelve of the twenty epileptic children were female, the age range was 3-13 years and the weight range was 12 to 79 kg. The dose received varied between 0.13-0.5 mg/kg. All of them were normal in renal and hepatic functions. Mean of the Cmax when observed for individual subjects was 264.07 +- 149.53 ng/mL after buccal administration while appeared to be 314.84 +- 180.33 ng/mL after rectal administration. There were no significant differences between the two routes of administration (P=0.184). 90% confident interval of Cmax ratio showed that Cmax after buccal administration was between 65% to 104% of rectal diazepam administration. Mean of time to reach Cmax (Tmax) after buccal administration was longer than after rectal route significantly (15.75 +- 7.83 and 11.5 +- 5.64 minutes, P=0.031). Absorption rate constant (Ka) was 21.81 +- 35.40 hour-1 for buccal route and 51.64 +- 76.91 hour-1 for rectal route with no statistical different between route of administration (P=0.153). No cardiovascular and respiratory toxicity was recorded in this study and the clinical efficacy could not be evaluated. There were two out of twenty patients after each route whose Cmax reached the target concentration for termination of seizure (500 ng/mL), both patients after buccal route and one patients after rectal route reached the target level within 5 minutes. There were 14 patients after buccal administration and 15 patients after rectal administration whose Cmax reached the level necessary to control seizures (200 ng/mL), two patients after buccal routeand five patients after rectal route reached the 200 ng/mL level within 5 minutes. Further study with higher dosage at the time of seizure should be performed to observe the true effects on clinical outcome. It seems feasible for buccal route to be use as an alternative to rectal route for diazepam administration in active seizure children especially after a better buccal formulation has been developed.