CARBAMAZEPINE AGE DOSE RATIO RELATIONSHIP IN CHILDREN

Steady-state plasma carbamazepine (CBZ) concentrations were measured in 196 pediatric inpatients taking CBZ alone or CBZ combined with other drugs. The steady-state CBZ concentrations divided by the daily administered dose (dose ratio, reciprocal of apparent clearance) increased significantly (r = 0.183, p < 0.01) with age. The correlation between dose and CBZ concentration, while significant (r = 0.265, p = 0.023), was weak because of wide interindividual differences in dose ratio. There was a negative correlation between CBZ daily dose and CBZ dose ratio. This negative correlation was significant in children 4-6 (r2 = 0.481, p < 0.01), 7-11 (r2 = 0.399, p < 0.01), and > 11 years of age (r2 = 0.401, p < 0.01), but not in children < 4 years of age (r2 = 0. 172, p > 0.1). The CBZ dose ratio was significantly (p < 0.001) lower in patients taking CBZ in combination with more than one other antiepileptic drug compared with those on CBZ monotherapy. No significant (p > 0.1) difference in CBZ dose ratio was found between male and female patients. These findings suggest that CBZ clearance was influenced by age, dose, and comedication with more than one other antiepileptic drug but not sex. The concentration necessary for efficacy is a clinical, not an analytical decision. However, the dose-concentration relationships show that recommended pediatric CBZ doses of 10-30 mg/kg/day are not enough to attain published therapeutic CBZ concentrations in many children. Increases in CBZ doses to > 30 mg/kg/day may be required even in children on monotherapy. However, prospective studies of the efficacy and toxicity of this regimen are required before it can be recommended.