Evaluation of Equations for Unbound Serum Concentration Prediction of Carbamazepine and Carbamazepine-10,11-epoxide in Polytherapy Pediatric Patients with Epilepsy

Abstract

We retrospectively evaluated the ability of equations with in vivo population binding parameters of our previous study (Method 1) or an average unbound fraction of 0.25 of Pynnönen (Method 2) to predict the unbound serum carbamazepine (CBZ) concentration in 50 serum samples from 28 polytherapy pediatric patients with epilepsy. In 12 serum samples from 10 patients, the ability of equations for unbound serum carbamazepine-10,11-epoxide (CBZ-E) concentration prediction was also determined in predictive performance with in vivo population binding parameters of our previous study (Method A) or an average unbound fraction of 0.5 of Pynnönen (Method B). Mean prediction error, mean absolute prediction error (MAE), and root mean squared error (RMSE) were calculated for each method, and these values served as a measure of prediction bias and precision. Method 1 shows a bias to underpredict unbound serum CBZ. The MAE and RMSE were lower in Method 2 (MAE = 0.696, μm, RMSE = 0.912 μM) than in Method 1 (MAE = 0.946 μM, RMSE = 1.138 μM). Method 2 is superior to Method 1 in accuracy and precision. The effects of antiepileptic co-medications on predictive performance of Method 1 are relatively larger in a co-medicated group of serum samples with valproic acid(n= 33, MAE = 0.994 μM, RMSE = 1.211 μM) than in a group of serum samples without valproic acid co-medication (n= 17, MAE = 0.853 μM, RMSE = 0.979 μM). Furthermore, the effects of the number of antiepileptic co-medications on predictive performance of Method 1 are relatively smaller in a group of serum samples of CBZ with one co-medication (n=17, MAE = 0.600 μM, RMSE = 0.682 μM) than in each group of those of CBZ with two (n= 16, MAE = 1.219 μM, RMSE = 1.378 μM) and with three to six co-medications (n= 17, MAE = 1.035 μM, RMSE = 1.246 μM). For unbound CBZ-E prediction, Method B has a bias to overprediction. The MAE and RMSE were lower in Method A (MAE = 0.267 μM, RMSE = 0.354 μM) than in Method B (MAE = 0.400μM, RMSE = 0.517 μM). Method A is superior to Method B in accuracy and precision.