A model for the determination of carbamazepine clearance in children on mono- 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 concentration measurements were gathered during normal routine care of 72 compliant out-patients (2.3–16.3 years old). Levels were obtained from patients receiving monotherapy (55%), concomitant valproate (26%), or concomitant 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 medication were all important determinants of clearance. The final model for clearance (l · 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 decreased with increasing age. As age and weight were correlated, either variable was a satisfactory predictor. The influence of both the inducers and valproate on CBZ clearance was as expected. This model, which describes clearance in terms of patient-specific details, can be used when predicting the maintenance dose required to achieve a target mean steady-state CBZ concentration in children. Received: 10 May 1997 / Accepted: 16 February 1998