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


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 doses are taken at one time.


RESULTS
Predicted plasma CBZ concentrations in this simulation fell from a trough of approximately 6.4 microg/ml only to 4 microg/ml after 24 h without medication, and only to 2.5 microg/ml after 36 h without medication. Predicted plasma CBZ concentrations in this simulation never rose above 9 microg/ml, indicating that taking missed doses of CBZ-ERC as soon as remembered, up to two missed doses 3 h 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.
Department of Pharmacy, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia 23298, USA. wrgarnet@vcu.edu
William R
WR
Garnett
Angus M
AM
McLean
Yuxin
Y
Zhang
Susan
S
Clausen
Simon J
SJ
Tulloch
D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002214:Capsules; D002220:Carbamazepine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003198:Computer Simulation; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D006801:Humans; D016312:Treatment Refusal
D000927:Anticonvulsants; D002214:Capsules; D003692:Delayed-Action Preparations; D002220:Carbamazepine