title: Bioequivalence of oral and intravenous carbamazepine formulations in adult patients with epilepsy.
abstract: OBJECTIVE
  To evaluate the safety, tolerability, and comparative pharmacokinetics (PK) of intravenous and oral carbamazepine.
  
  
  METHODS
  In this phase 1, open-label study, adult patients with epilepsy on a stable oral carbamazepine dosage (400-2,000 mg/day) were converted to intravenous carbamazepine (administered at 70% of the oral dosage). A 28-day outpatient period preceded an up to 10-day inpatient period and a 30-day follow-up period. Intravenous carbamazepine was administered over 15 or 30 min every 6 h on days 1-7; some patients in the 15-min group were eligible to receive four 2- to 5-min (rapid) infusions on day 8. Patients underwent blood sampling to determine the area under the concentration-time curve (AUC) for carbamazepine and metabolite carbamazepine-10,11-epoxide following oral (day 0) and intravenous carbamazepine administration (days 1, 7, and 8). Bioequivalence was evaluated in patients with normal renal function (creatinine clearance >80 ml/min). Safety assessments were conducted through day 38.
  
  
  RESULTS
  Ninety-eight patients enrolled and 77 completed the PK component. The mean daily oral and intravenous carbamazepine dosage for 64 PK-evaluable patients with normal renal function was 962.5 and 675.1 mg (70% of oral dosage), respectively. Steady-state minimum concentration (C(min)) and overall exposure (AUC0-24) for intravenous carbamazepine infused over 30, 15, or 2-5 min were similar to oral carbamazepine. The 90% confidence intervals (CIs) for the ratios of the adjusted means for AUC0-24, maximum concentration (Cmax), and C(min) were within the 80%-125% bioequivalence range for 30-min intravenous infusions versus oral administration, but exceeded the upper limit for Cmax for the 15-min and rapid infusions. All intravenous carbamazepine infusions were well tolerated.
  
  
  CONCLUSIONS
  Intravenous carbamazepine infusions (70% of oral daily dose) of 30-, 15-, and 2- to 5-min duration, given every 6 h, maintained patients' plasma carbamazepine concentrations. Intravenous carbamazepine 30-min infusions were bioequivalent to oral carbamazepine in patients with normal renal function; rapid infusions were well-tolerated in this study.
authors.affiliation: Lundbeck LLC, Deerfield, Illinois, U.S.A.
authors.forename: Dwain
authors.initials: D
authors.lastname: Tolbert
authors.affiliation: Center for Orphan Drug Research, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, U.S.A.
authors.forename: James
authors.initials: J
authors.lastname: Cloyd
authors.affiliation: Arkansas Epilepsy Program, Little Rock, Arkansas, U.S.A.
authors.forename: Victor
authors.initials: V
authors.lastname: Biton
authors.affiliation: Lundbeck LLC, Deerfield, Illinois, U.S.A.
authors.forename: Ihor
authors.initials: I
authors.lastname: Bekersky
authors.affiliation: Lundbeck LLC, Deerfield, Illinois, U.S.A.
authors.forename: Mark
authors.initials: M
authors.lastname: Walzer
authors.affiliation: Lundbeck LLC, Deerfield, Illinois, U.S.A.
authors.forename: David
authors.initials: D
authors.lastname: Wesche
authors.affiliation: Lundbeck LLC, Deerfield, Illinois, U.S.A.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Drummond
authors.affiliation: Lundbeck LLC, Deerfield, Illinois, U.S.A.
authors.forename: Deborah
authors.initials: D
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000097:blood; D019540:Area Under Curve; D002220:Carbamazepine / Q000008:administration & dosage* / Q000097:blood; D064420:Drug-Related Side Effects and Adverse Reactions; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine
keywords: Bioequivalence; Cyclodextrin; Epilepsy; Intravenous carbamazepine; Pharmacokinetic