A limited sampling method for the estimation of AUC and Cmax of carbamazepine and carbamazepine epoxide following a single and multiple dose of a sustained-release product.
OBJECTIVE
The objectives of this study are to develop a model to predict area under the curve (AUC) and maximum plasma concentration (Cmax) of carbamazepine (CBZ) and its active metabolite carbamazepine epoxide (CBZE) following single and multiple dose of CBZ using one or two samples in volunteers.


METHODS
Limited sampling models (LSM) were developed for CBZ and CBZE following 200-800 mg single oral dose and 400-800 mg twice daily dose for 14 days of a sustained-release product (CBZ-SR) to estimate AUC and Cmax. The LSM was developed from a training data set of 15 subjects using one blood sample taken at 48 h following a single dose. The model was validated on 60 subjects who received different doses of CBZ. Following multiple dosing, the LSM was developed from a training data set of 10 subjects using the steady state Cmin (plasma concentration obtained 5 min before the last CBZ-SR dose).


RESULTS
The model provided good estimates of AUC and Cmax for CBZ and CBZE. The bias and the precision of the predicted AUC and Cmax for CBZ and CBZE were less than 10% and 15%, respectively. Similar results were obtained when CBZ was given as multiple dose.


CONCLUSIONS
The method described here may be used to estimate AUC and Cmax for CBZ and CBZE without detailed pharmacokinetic studies following single or multiple dose of CBZ.
Mahmood
I
I
Office of Clinical Pharmacology and Biopharmaceutics, Division of Pharmaceutical Evaluation I. Food & Drug Administration, Rockville, MD 20852, USA.
Chamberlin
N
N
D000284:Administration, Oral; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D008297:Male
D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D002220:Carbamazepine; C012227:carbamazepine epoxide