Pilot Bioavailability Study Comparing Intramuscularly Administered Stable-Labeled Fosphenytoin in Adults and Elderly Patients
Abstract number :
1.285
Submission category :
Year :
2001
Submission ID :
3038
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
L.C. Musib, Ph.D., College of Pharmacy, University of Minnesota, Minneapolis, MN; J.C. Cloyd, Pharm.D., College of Pharmacy, University of Minnesota, Minneapolis, MN; A.K. Birnbaum, Ph.D., College of Pharmacy, University of Minnesota, Minneapolis, MN; I.E
RATIONALE: Phenytoin (PHT) is the most commonly prescribed antiepileptic drug in the elderly. We are studying PHT pharmacokinetics (PK) in elderly patients using stable-labeled PHT given intravenously or stable-labeled fosphenytoin (FOS) given intramuscularly. The purpose of this study is to determine and compare the bioavailability of stable-labeled FOS in adults and elderly patients and determine if the two stable isotopes are kinetically equivalent.
METHODS: Patients on steady-state maintenance PHT therapy were given a single100 mg intravenous injection of [2-13C-1,3-15N2] 5,5-diphenylhydantoin (stable-labeled PHT) and a 100 mg phenytoin equivalent intramuscular injection of [2, 4, 5-13C-1,3-15N2] 5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4-imidazolidinedione disodium salt (stable-labeled FOS) as part of their daily regimen. Patients taking potentially interacting co-medications were excluded. Blood samples were collected just prior to and up to 192 hours after the isotope doses. PHT derived from IM FOS is 5 mass units greater than unlabeled PHT and 2 mass units greater than the labeled PHT. Unlabeled PHT, 3-labeled PHT and 5-labeled PHT were measured using a gas chromatographic-mass spectrometric assay. Unbound drug was separated from total PHT by ultrafiltration. Bioavailability was measured using the area under the plasma concentration time curves. Non-compartmental PK analysis was done with WinNonlin 3.0.
RESULTS: One elderly and three younger adults have been studied to date. Pharmacokinetic data from two adults are shown in the table.[table]
CONCLUSIONS: We plan to enroll five young adults and five elderly patients for this pilot study. The PK values from the labeled PHT are similar to the PK values from the labeled FOS indicating pharmacokinetic equivalency. The absorption of intramuscular FOS was complete in adults. Previous reports in the elderly have shown that IM administration of FOS is safe and well tolerated. From our results, it is evident that stable-labeled FOS can be used in place of stable-labeled PHT. If bioavailability studies in our elderly subjects confirm complete absorption and safety, our stable-labeled FOS formulation can be used in nursing home residents including frail elderly for PHT PK studies.
Support: Supported by NIH-NINDS P50-NS16308, M01-RR00400 and in part by Pfizer, Inc.
Disclosure: Grant - Pfizer, Inc.