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

ABSTRACT

Objective: Plasma concentrations of antiepileptic drugs (AEDs) can vary and are not always an indication of clinical utility. However, adverse event occurrence can be correlated to fluctuations in plasma drug levels that occur with varying dosing regimens of the many AEDs. In this study, we present the results of computer simulations of plasma concentrations of the AEDs carbamazepine (CBZ) extended-release capsules (CBZ‐ERC) (Carbatrol) and oxcarbazepine (OXC).

* Carbatrol is a registered trade name of Shire, Wayne, Pa, USA

Research design and methods: A one-compartment open model with first-order absorption and elimination was generated from the results of a previous study measuring plasma concentrations following one 400 mg fasting dose of CBZ‐ERC. This model was used to simulate plasma concentrations of CBZ following multiple 400 mg doses of CBZ‐ERC at 12-hour intervals, and then when a missed dose is taken 3, 6, or 9 hours late; when two doses are taken at one time; and when a single dose is taken at the time of the next dosing. In comparison, similar modeling was done for monohydroxy derivative (MHD) of OXC at doses of 600 or 1200 mg.

Results: Plasma drug concentrations after 24 hours without medication were 4.1 mg/L for CBZ‐ERC, 8 mg/L for 600 mg OXC, and 16 mg/L for 1200 mg OXC. If a patient was to take only a single dose 24 hours late, it would take 24 hours to reach steady-state trough values for CBZ‐ERC, 36 hours for 600 mg OXC, and 2 days for 1200 mg OXC. The trough plasma concentration following a missed dose and the peak plasma concentration following a double dose (administered 12 hours after the missing of a dose) differed by a factor of two in the CBZ‐ERC simulation, compared with a factor of three in both OXC simulations.

Conclusions: The ultimate goal of antiepileptic therapy is a seizure-free state without side effects. The current computer simulation study indicates that AEDs such as CBZ‐ERC and OXC, which produce relatively stable plasma concentrations, should be useful in attaining this goal. Nonetheless, simulated plasma concentrations resulting from CBZ‐ERC treatment tended to oscillate less dramatically compared with simulated plasma concentrations resulting from treatment with 600 or 1200 mg OXC.

Key words: :

• Carbamazepine
• Dosing
• Extended
• Models
• Oxcarbazepine

Notes

* Carbatrol is a registered trade name of Shire, Wayne, Pa, USA