Controlled, multidose, pharmacokinetic evaluation of two extended-release carbamazepine formulations (carbatrol and tegretol-XR)

Abstract

A major limitation of conventional carbamazepine (CBZ) formulations is their pharmacokinetics, which typically require q.i.d. dosing. Two extended-release formulations of CBZ have been developed recently to support b.i.d. dosing. One, Carbatrol (CBTL) uses immediate-, extended-, and enteric-release beads in a capsule. The other, Tegretol-XR (TXR), uses an osmotic pump (Oros tablet). To our knowledge, this is the first head-to-head comparison of the multidose pharmacokinetics of these two new formulations. The objective of the study was to evaluate the pharmacokinetics of carbamazepine (CBZ) and CBZ-10,11-expoxide (CBZ-E) after multidose b.i.d. dosing with CBTL or TXR. In this randomized, crossover study, 15 normal healthy adults received 400 mg of each formulation b.i.d. for 5 days. Blood samples for CBZ and CBZ-E analysis were obtained prior to morning doses on all days and hourly for 12 h after the Day 5 dose. There was a minimum interperiod washout of 9 days. For CBTL and TXR, the key CBZ pharmacokinetic measures of area under the curve of concentration versus time (AUC(0-tau)), maximum concentration (Cmax), and minimum concentration (Cmin) were bioequivalent. The ratio for CBTL-to-TXR was 98% (90% confidence intervals, 92-104%), 107% (96-118%), and 96% (89-104%), respectively. Similar ratios were also observed for CBZ-E: 102% (97-107%), 99% (92-107%), and 93% (83-109%), respectively. In conclusion, CBTL b.i.d. and TXR b.i.d. were bioequivalent in their pharmacokinetic parameters for CBZ and CBZ-E after 5 days of dosing.

Extended‐release antiepileptic drugs: A comparison of pharmacokinetic parameters relative to original immediate‐release formulations

“…Carbatrol is formulated using Microtrol technology and is composed of a mixture of IR, ER, and enteric‐release beads within a capsule. The capsule can be swallowed whole or can be opened and sprinkled on food, a feature of particular benefit to patients who have difficulty swallowing (Stevens et al., 1998). Tegretol‐XR is formulated using the OROS technology, which depends on gastric absorption of osmotically drawn water, forcing carbamazepine out of the tablet with hydrostatic pressure (Tegretol OROS Study Group, 1995).…”

“…The two‐branded ER formulations of carbamazepine noted above, administered twice daily, were compared in a small head‐to‐head crossover study and, although both formulations are bioequivalent to IR carbamazepine administered four times daily, some PK differences were noted (Stevens et al., 1998). For carbamazepine, the coefficient of variability for AUC 0‐τ was 20% for Tegretol‐XR and 12% for Carbatrol, suggesting that the latter product is more predictably delivered.…”

Studies of Carbamazepine Extended-Release Capsules in Bipolar Disorder

“…Minimizing the fluctuations in serum CBZ concentrations inherent in immediate-release formulations was an important factor in the development of CBZ-ERC. Low peak-to-trough blood level variability ensures that blood CBZ levels remain relatively stable (Stevens et al 1998). In studies of CBZ in patients with epilepsy, conversion from immediate- to extended-release CBZ resulted in marked reductions in common dose-related CNS side effects.…”

Improved solubilization of carbamazepine and structural transitions in nonionic microemulsions upon aqueous phase dilution

“…The drug was originally evaluated for treating trigeminal neuralgia, but based on clinical experience it became the drug of choice for all partial and for tonic-clonic seizures [3]. CBZ is traditionally administered orally as a solid, but due to its low solubility in water (about 170 mg/l at 24 • C) [4] its gastrointestinal absorption is slow and irregular [5,6], leading to incomplete bioavailability.…”

“…CBZ is traditionally administered orally as a solid, but due to its low solubility in water (about 170 mg/l at 24 • C) [4] its gastrointestinal absorption is slow and irregular [5,6], leading to incomplete bioavailability. There is also considerable variability in CBZ plasma concentration [3,6,7].…”