Pharmacokinetic Evaluation of Twice‐Daily Extended‐Release Carbamazepine (CBZ) and Four‐Times‐Daily Immediate‐Release CBZ in Patients with Epilepsy

Abstract

Summary: Purpose:A new capsule dosage form of carbamazepine (CBZ) has been developed, consisting of three different types of beads (immediate-release, extended-release, and enteric-release) that may be taken sprinkled on food or swallowed for easy administration. We compared the pharmacokinetics of the extended-release dosage form of CBZ (Carbatrol capsules) twice daily with the conventional immediate-release formulation of CBZ four times daily.Methods: The randomized, double-blind, two-way, crossover study was conducted at two sites, with a planned sample size of 24 adult patients with epilepsy. Each treatment was administered for 2 weeks. At the end of the 2-week period, blood samples were obtained hourly for a 24-h period.Results: The 90% confidence intervals (CI) of the ratio of the means of the extended-release formulation twice daily to the immediate-release formulation four times daily were within the range of 0.80-1.25 for each of the pharmacokinetic parameters for CBZ and for the summation of CBZ and CBZ-epoxide (CBZ-E). There was no difference in the frequency of seizures between treatment (p = 0.103).Conclusions: Our results demonstrate that extended-release CBZ twice daily was bioequivalent to immediate-release CBZ four times daily, with regard to CBZ levels and summation of CBZ and CBZ-E levels, based on the pharmacokinetic parameters evaluated. Substituting one formulation for the other did not cause patients to have a significant change in seizure frequency. Key Words: Carbamazepine-PharmacokineticsExtended release-Epilepsy.Since its first introduction into clinical use for the treatment of epilepsy in the 1970s (1-3), carbamazepine (CBZ) has become a drug of choice for the treatment of simple partial, complex partial, and secondarily generalized tonic-clonic seizures (SPS, CPS, SGTCS). The conventional immediate-release forms of CBZ, require frequent (three or four times daily) dosing, however, and variability in CBZ drug levels in the blood has been reported. Both of these issues are problematic (4-6).Adherence to a medication regimen is a major issue in the pharmacological treatment of epilepsy, with studies frequently linking seizures to poor adherence. Adherence can be affected by both the frequency of drug administration as well as the occurrence of side effects, frequently linked to blood levels of drug. Additional factors affecting adherence to a regimen by patients with epilepsy may be memory difficulties and frequent seizures. In studies from several centers, adherence to antiepileptic drug (AED) dosing regimens ranged from 39 to 82% (7)(8)(9)(10)(11). In a study of patients with epilepsy using electronic compliance monitors, adherence to a once-or twice-daily regimen was -80%, as contrasted with -40% adherence to a four-times-daily regimen (12). A patient's variable adherence to an AED regimen can lead to increased variability in blood levels (1 3). One of the issues involved in the dosing of CBZ is its high degree of insolubility and variations in bioavailability. Peak-to-trough fluctu...

The effect of poor compliance on the pharmacokinetics of carbamazepine and its epoxide metabolite using Monte Carlo simulation

“…It was reported that a twice-daily CBZ extended-release preparation can maintain small fluctuations of peak-to-trough within a dosing interval and may result in good tolerability in epilepsy patients [34,35] . Because its population pharmacokinetics were not well established, further research may be needed.…”

Studies of Carbamazepine Extended-Release Capsules in Bipolar Disorder

“…In a pharmacokinetic study conducted in patients with epilepsy, twice-daily CBZ-ERC was shown to be bioequivalent to immediate-release formulations of CBZ given four times daily (Garnett et al 1998). Minimizing the fluctuations in serum CBZ concentrations inherent in immediate-release formulations was an important factor in the development of CBZ-ERC.…”

Carbamazepine extended-release capsules vs. oxcarbazepine: computer simulations of the effect of missed doses on drug plasma concentrations

“…Thus, most patients time their QID regimens so as to take their medications around mealtimes and bedtime, making dosing intervals during the day shorter than ideal, with resultant plasma concentrations higher during the day and lower at night. Furthermore, there is an increased potential for doserelated side effects at times when patients are most likely to find them disruptive and disquieting 3 .…”

“…This has led to the development of CBZ extended-release capsules (CBZ-ERC) (Carbatrol*) that rely on a proprietary drug delivery system using a mixture of immediate-release, extended-release, and enteric-release beads. A recent double-blind, randomized, cross-over evaluation has demonstrated that twice-daily CBZ-ERC is equivalent to rigidly dosed (Q6h) four times daily IR-CBZ (as measured by plasma levels of CBZ and CBZ-epoxide) 3 . In addition, a 6-month, open-label study showed that patients could be switched on a milligram for milligram basis from IR-CBZ to CBZ-ERC, not only with no loss of seizure control, but with an improved quality of life 6 subsequently attributed to, among other factors, fewer CBZ-related adverse effects with CBZ-ERC than with the immediate-release form 7 .…”