A MODEL FOR THE DETERMINATION OF CARBAMAZEPINE CLEARANCE IN CHILDREN ON MONOTHERAPY AND POLYTHERAPY

Objective. To derive a model describing carbamazepine (CBZ) clearance in children, in terms of individual patient characteristics. Methods. One hundred and eighteen steady-state serum carbamazepine concentratio n measurements were gathered during normal routine care of 72 complian t outpatients (2.3-16.3 years old). Levels were obtained from patients receiving monotherapy (55%), concomitant valproate (26%), or concomit ant inducers (phenytoin, phenobarbitone; 19%). A one-compartment model was used to fit the data with the computer programme Nonlinear Mixed Effects Model (NONMEM). Results. Weight, age and concomitant medicatio n were all important determinants of clearance. The final model for cl earance (1 . h(-1)) was: CL = [0.7(WT)(0.4)] . M, where WT is patient weight (kg) and M is a scaling factor for concomitant medication, with a value of 1 for patients on CBZ monotherapy or concomitant valproate and 1.4 for those receiving concomitant inducers. For the purposes of this analysis, bioavailability (f) was assumed to be complete, i.e., f is thus included in the term CL. Conclusions: CBZ clearance decrease d with increasing age. As age and weight were correlated, either varia ble was a satisfactory predictor. The influence of both the inducers a nd valproate on CBZ clearance was as expected. This model, which descr ibes clearance in terms of patient-specific details, can be used when predicting the maintenance dose required to achieve a target mean stea dy-state CBZ concentration in children.