Epilep.psia, zyxwvutsrqponml 41(7):850-853, zyxwvutsrqponmlk 2000 Lippincott Williams & Wilkins, lnc., Baltimorc zyxwvutsrqpo 0 International League Against Epilepsy Clinical Research Rectal Absorption of Lamotrigine Compressed Tablets *?Angela K. Birnbaum, *$Robert L. Kriel, *R. Todd Burkhardt, and TRory P. Remmel "Experimental and Clinical Pharmacology and fMedicinal Chemistry, Epilepsy Research and Education Program, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota; and $Departments zyxwv of Pediatrics and Neurology, Hennepin County Medical Center, Minneapolis, Minnesota, and Gillette Children's Specialty Healthcare, St. Paul, Minnesota, zyx U.S.A. zyx Summary: Purpose: Interruption of oral drug administration poses a significant clinical problem for antiepileptic drugs that have no parenteral formulation. If a drug is absorbed rectally, rectal administration can be a useful alternative when the oral route of administration is not possible. The purpose of this study was to compare the single-dose pharmacokinetics of la- motrigine (LTG) compressed tablets after rectal and oral ad- ministration in healthy volunteers. Methods: A single LTG compressed tablet (100 mg) was administered orally and rectally to 12 volunteers in this single- dose, two-period, crossover study with a 2-week washout be- tween doses. For rectal administration, tablets were crushed and suspended in 10 mL of water. Plasma samples were col- lected from 0 to 120 hr after each dose and analyzed for LTG by an HPLC method developed for this investigation. Results: LTG plasma concentrations were lower after rectal administration versus oral administration. The average area un- der the curve was 28.90 * 9.5 p,g/mL/hr after rectal adminis- tration and 51.71 zyxwv f 19.2 pg/mL/hr after oral administration. The average maximum LTG concentration was 0.53 & 0.14 pg/mL after rectal administration and 1.45 +. 0.35 pg/mL after oral administration. The relative bioavailability for LTG com- pressed tablets was 0.63 & 0.33 for rectal administration. There were no drug-related rashes or serious side effects. Conclusions: LTG suspension prepared from LTG com- pressed tablets is absorbed rectally, although not to the same extent or rate as when given orally. Key Words: Lamo- trigine-Rectal-Bioavailability-Compressed-Antiepi- leptic. Lamotrigine (LTG) is an antiepileptic drug (AED) ap- proved for use in adults with partial seizures and in pe- diatrics and adults for the treatment of generalized sei- zures of Lennox-Gastaut syndrome. Currently, LTG is available in two formulations: an oral compressed tablet (25, 100, 150, and 200 mg) and a chewable dispersible tablet (5 and 25 mg). No parenteral formulation is avail- able; therefore LTG therapy cannot be continued when a patient is vomiting, undergoing surgery, or experiencing gastrointestinal illness. Interruption of LTG administra- tion increases the risk of increased seizure activity during these episodes. Alternative routes of administration, in- cluding the rectal route, are needed to minimize seizure risk when patients cannot take LTG by mouth. hyde (7)). Some AEDs should not be given rectally be- cause of poor solubility in aqueous solutions. For ex- ample, the relative bioavailabilities of gabapentin (8) and phenytoin (9) were low after rectal administration with current formulations, thus making them unsuitable for this route. The purpose of this study was to compare the single- dose pharmacokinetics of LTG compressed tablets for- mulated as an aqueous suspension and administered rec- tally to the pharmacokinetics after oral administration of compressed tablets in healthy volunteers. METHODS The rectal route of administration has been studied for several AEDs (valproate (l), carbamazepine (2), loraze- Study design Twelve healthy subjects between the ages of 18 and 65 randomized, two-period, crossover study. The study was Pam (3), diazepam (4,5), phenobarbital (6), and paralde- years (40.8 11.5 years) were enrolled in a single-blind, Accepted January 31, 2000. approved by the Institutional Review Board/Human Sub- birnb002@tc.umn.edu tained from each subject. Qualified subjects were asked 850