Population pharmacokinetics of carbamazepine in Singapore epileptic patients

Abstract

Aims: To document the population pharmacokinetics of carbamazepine in patients with epilepsy living in Singapore, the majority of whom are of Chinese origin and others of minority races.

Methods: Steady-state plasma carbamazepine concentration data were gathered during routine care from various hospitals in Singapore for patients with epilepsy. Age, body weight, gender, race, formulation and concurrent medication (for other illnesses) were the fixed effects (covariates) tested simultaneously for their influence on the population mean of carbamazepine clearance, using the nonlinear mixed-effects model, in the NONMEM program.

Results: No age, gender, race, or formulation-related effect was found. Body weight (W), age (A) and concurrent medication with phenobarbitone (PB) emerged as the determinants of carbamazepine clearance (CL). The final regression model for carbamazepine clearance found best to describe the data was CL = 40.7 x A(0.494) x W(-1.17) x 1.44PB where CL is in l day(-1) kg(-1), A is in years, W is in kg and PB = 0 for a patient on carbamazepine only and PB = 1 for a patient on concomitant PB. The corresponding interindividual variability (CV%) in CL, described by using an exponential model, was 21.4%, and the residual error, described by using an exponential error model, was 18.2%. Predictive performance of this population covariate model was evaluated by Bayesian forecasting in a similar, but independent cohort of patients. There was no statistically significant bias between predicted and measured plasma carbamazepine concentrations. The population mean value of carbamazepine clearance obtained was similar to that previously reported for patients with a very different ethnic (Caucasians and Blacks) or geographical background (South Africa, Europe and USA).

Conclusions: The derived covariate regression model reasonably predicted concentrations in the separate validation Singapore patient data set. The correlation between carbamazepine clearance and patient-specific characteristics may thus allow dosage adjustment to be made to achieve target steady-state plasma concentrations.

Figure 1

Mean plasma carbamazepine concentration to dose (L/D) ratios in various age groups (± s.e. mean). Age group: 1 (1–24 months); 2 (2–12 years,11 months); 3 (13–19 years, 11 months); 4 (20–51 years). *significantly different from age group 1, **significantly different from age group 1 and 2. (P < 0.05, using one-way anova: Post hoc multiple comparison-LSD test.

Figure 2

a) Scatter plot of observed carbamazepine concentration vs final covariate model-predicted concentration. b) Plot of residual vs final covariate model-predicted concentration.