Population pharmacokinetics modeling of levetiracetam in Chinese children with epilepsy

Abstract

Aim: To establish a population pharmacokinetics (PPK) model of levetiracetam in Chinese children with epilepsy.

Methods: A total of 418 samples from 361 epileptic children in Peking University First Hospital were analyzed. These patients were divided into two groups: the PPK model group (n=311) and the PPK validation group (n=50). Levetiracetam concentrations were determined by HPLC. The PPK model of levetiracetam was established using NONMEM, according to a one-compartment model with first-order absorption and elimination. To validate the model, the mean prediction error (MPE), mean squared prediction error (MSPE), root mean-squared prediction error (RMSPE), weight residues (WRES), and the 95% confidence intervals (95% CI) were calculated.

Results: A regression equation of the basic model of levetiracetam was obtained, with clearance (CL/F)=0.988 L/h, volume of distribution (V/F)=12.3 L, and K(a)=1.95 h(-1). The final model was as follows: K(a)=1.56 h(-1), V/F=12.1 (L), CL/F=1.04×(WEIG/25)(0.583) (L/h). For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95%CI were 9.834 (-0.587-197.720), 50.919 (0.012-1286.429), 1.680 (0.021-34.184), and 0.0621 (-1.100-1.980). For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were 0.199 (-0.369-0.563), 0.002082 (0.00001-0.01054), 0.0293 (0.001-0.110), and 0.153 (-0.030-1.950).

Conclusion: A one-compartment model with first-order absorption adequately described the levetiracetam concentrations. Body weight was identified as a significant covariate for levetiracetam clearance in this study. This model will be valuable to facilitate individualized dosage regimens.

Figure 1

Scattergram of concentrations and intervals between the last dosage time and the sampling time of patients. (A) the PPK model group. (B) the PPK validation group.

Figure 2

Frequency of intervals between the last dose and sampling time in the model group.

Figure 3

Diagnostic plots of the final PK model. (A) Plot of the observed concentrations versus population predicted levetiracetam concentrations (PRED). B) Plot of the observed concentrations versus individual population predicted levetiracetam concentrations (IPRED). (C) Plot of population predicted levetiracetam concentrations (PRED) versus CWRES. (D) Plot of CWRES versus TIME. DV: Dependent Variable.