Simulation of the effect of patient nonadherence on plasma concentrations of carbamazepine from twice-daily extended-release capsules

Abstract

SUMMARYObjective: Carbamazepine (CBZ) effectively treats simple, complex, and secondarily generalized partial seizures. Computer simulations were carried out to investigate the effect of missing or delaying doses of carbamazepine extended-release capsules (CBZ-ERC) on plasma CBZ levels and the optimal dosing strategy to return plasma concentrations to therapeutic levels.Patients 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. The model was used to simulate plasma CBZ concentrations following multiple doses given every 12 h to hypothetical long-term CBZ-treated patients, with the CBZ elimination half-life set to 13.7 h to account for enzymatic autoinduction. The model was then used to simulate plasma CBZ concentrations when a dose is taken 3,6, or 9 h late, or when two dosesare taken at one time.Results: Predicted plasma CBZ concentrations in this simulation fell from a trough of approximately 6.4μg/ml only to 4 μg/ml after 24 h without medication, and only to 2.5μg/ml after 36h without medication. Predicted plasma CBZ concentrations in this simulation never rose above 9|ig/ml, indicating that taking missed doses of CBZ-ERC as soon as remembered, up to two missed doses 3h before taking the next scheduled dose, will not lead to harmful spikes in plasma concentrations of CBZ.Conclusions: The simulations suggest that taking a missed dose of CBZ-ERC as soon as remembered, up to two doses at one time, may be the best strategy to return plasma CBZ concentrations to steady-state levels. Since the model used in this study is a simplified model of a highly complex situation, caution should be used when relating these results to clinical practice until trials are conducted in patients.