Abstracts

RATIONALE: Carbamazepine extended-release capsules (CBZ-ERC) twice daily have been demonstrated to be effective in the treatment of seizure disorders. Although twice-daily dosing regimens are consistently associated with improved levels of patient adherence, doses will still be missed and patients will ask clinicians if or when to take the missed dose. The objective of the current computer simulations was to assist in the development of recommendations by investigating both the effect of missing doses on plasma CBZ levels and the optimal dosing strategy to return plasma concentrations to normal steady-state levels.
METHODS: Mean plasma concentrations measured in a previous study following treatment with one dose of 400 mg Carbatrol (CBZ-ERC) were fitted to a one-compartment mathematical model. This model was then used in the simulation of plasma concentrations following 400 mg every 12 hours, allowing for the enzyme induction that occurs following multiple doses of CBZ. Simulations of several possible situations were carried out that included missing either one or two doses and then alternatively: skipping the dose(s) completely, taking the missed dose 3 hours later, taking the missed dose 9 hours later, or taking two doses at the time of the next scheduled dose.
RESULTS: All of the simulations indicate that taking the missed dose of CBZ-ERC as soon as it is remembered, up to two missed doses 3 hours before the next scheduled dose, will not lead to potentially harmful spikes in plasma levels of CBZ. The simulations also indicated that the trough after missing one dose of CBZ-ERC would remain about 4 mcg/mL. A simulation of the plasma concentration after missing one dose and contrasted to taking 2 at the time of the next scheduled dose is shown below. Solid line indicates simulated steady-state plasma concentrations of CBZ. Dotted line indicates simulated plasma concentrations of CBZ upon taking the missed dose combined with the next scheduled dose and continuing with dosing regimen. Arrow indicates time of missed dose. Dashed lines indicate the typical target range for CBZ concentration.
CONCLUSIONS: With conventional, immediate-release tablets of CBZ, it is recommended that a missed dose not be taken too close in time to the next scheduled dose due to concerns about spikes in plasma drug levels and resultant side effects. It is essential to stress the importance of medication adherence when counseling patients with epilepsy, regardless of which medication or formulation they have been prescribed. The current computer simulations of missing a dose or doses of CBZ-ERC suggest that when a dose is occasionally missed, taking it as soon as it is remembered, even when this implies taking two doses at one time, would not only be safe but would be the best strategy to return plasma concentrations of CBZ to steady-state levels. This may be due to the unique extension of release provided by the Microtol[tm] release system.[figure1]
[Supported by: Shire US Inc.]; (Disclosure: Salary - A. McLean, Shire, Grant - W. Garnett, Shire, Equity - A. McLean, Shire, Consulting - A. McLean, Shire, Stock - A. McLean, Shire, Honoraria - W. Garnett, Shire)