PRELIMINARY REPORT ON CARBAMAZEPINE PHARMACOKINETICS IN PATIENTS WITH EPILEPSY GIVEN A PARENTERAL FORMULATION
Abstract number :
1.285
Submission category :
Year :
2002
Submission ID :
3526
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Luna C. Musib, James C. Cloyd, Jeannine M. Conway, Angela K. Birnbuam, Flavia M. Pryor, R. Eugene Ramsay, Rory P. Remmel, Gregory S. Holden, John O. Rarick, James R. White, Ilo E. Leppik. Global Pharmacokinetics, Eli Lilly, Indianapolis, IN; College of Ph
RATIONALE: Carbamazepine (CBZ) is a widely prescribed antiepileptic drug exhibiting complex pharmacokinetics (PK) which complicate its use. Although extensively studied, there are no reports describing absolute bioavailability and elimination half life in patients under steady-state conditions. One obstacle to conducting such studies is the lack of a parenteral CBZ formulation. We have developed an investigational, intravenous, stable-labeled CBZ formulation in order to rigorously characterize steady-state CBZ PK in adult and elderly patients. The purpose of the present study was to obtain preliminary CBZ PK information in adults.
METHODS: Adults 18 years or older with epilepsy on maintenance CBZ therapy were eligible to participate in the study. Exclusion criteria included presence of significant cardiac problems or use of potentially interacting co-medications. On the day of the study, patients were given a single 100 mg intravenous infusion of a 5H-dibenz[b,f]azepine-5-,13C, 15N-carboxamide (SL-CBZ) formulation as part of their morning dose. The remainder of the dose was given orally. Blood samples were collected just prior to and up to 96 hours after SL-CBZ administration. Both CBZ and SL-CBZ were measured in plasma using LC-MS. Unbound drug was separated from total CBZ by ultrafiltration. Non-compartmental PK analysis was done with WinNonlin 3.0.
RESULTS: Seven patients (3 females and 4 males) ranging in age from 34 to 53 years have completed the study. CBZ daily doses ranged from 400-2400 mg. Daily dose and PK information are included in the table below:[table1]
CONCLUSIONS: CBZ induces its own metabolism, as a result CBZ PK determined following a single dose cannot be extraprolated to steady-state conditions. This is the first study using a parenteral formulation to rigorously characterize CBZ PK in patients on maintenance therapy. Our preliminary results indicate that there is wide inter-patient variability in CBZ bioavailability and elimination half-life, whereas distribution volume is relatively constant. Use of a parenteral SL-CBZ formulation permits comprehensive characterization of the effects of age, gender, co-medications and genotype on CBZ PK in patients without interrupting therapy.
[Supported by: NIH-NINDS P50-NS16308 and M01-RR00400.]; (Disclosure: Consulting - Novartis, Honoraria - Novartis)