Population pharmacokinetic modeling of oxcarbazepine active metabolite in Chinese patients with epilepsy

Abstract

The aim of the study was to develop a population pharmacokinetic (PPK) model of oxcarbazepine and optimize the treatment of oxcarbazepine in Chinese patients with epilepsy. A total of 108 oxcarbazepine therapeutic drug monitoring samples from 78 patients with epilepsy were collected in this study. The pharmacologically active metabolite 10,11-dihydro-10-hydrocarbamazepine (MHD) was used as the analytical target for monitoring therapy of oxcarbazepine. Patients' clinical data were retrospectively collected. The PPK model for MHD was developed using Phoenix NLME 1.2 with a non-linear mixed-effect model. MHD pharmacokinetics obeys a one-compartment model with first-order absorption and elimination. The effect of age, gender, red blood cell count, red blood cell specific volume, hemoglobin (HGB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatine were analyzed. Bootstrap and data splitting were used simultaneously to validate the final PPK models. The mean values of volume of distribution and clearance of MHD in the patients were 14.2 L and 2.38 L h(-1), respectively. BUN and HGB influenced the MHD volume of distribution according to the following equation: V = tvV × (BUN/4.76)(-0.007) × (HGB/140)(-0.001) × e (ηV) . The MHD clearance was dependent on ALT and gender as follows: CL = tvCL × (ALT/30)(0.181) × (gender) × 1.083 × e (ηCL). The final PPK model was demonstrated to be suitable and effective and it can be used to evaluate the pharmacokinetic parameters of MHD in Chinese patients with epilepsy and to choose an optimal dosage regimen of oxcarbazepine on the basis of these parameters.

Population pharmacokinetics and dose simulation of oxcarbazepine in Chinese paediatric patients with epilepsy

“…The typical population values of the PK parameters of the final model were as follows: TVCL = 3.25 L/h/70 kg, TVV = 151.41 L/70 kg, and Ka = 0.598 h −1 . TVCL in this study was within the range calculated in the existing models (2.37‐4.11 L/h/70 kg) and was very close to those found in the researches by Rodrigues et al (3.18 L/h/70 kg for children not taking EI) and Sallas et al (3.2 L/h/70 kg), while TVV was similar to those of Sugiyama et al (171.5 L/70 kg). Ka was fixed according to studies by Park et al and Sallas et al, consistent with previous models (0.41‐0.83 h −1 ) .…”

“…Although several studies have established OXC and MHD PPK models, some were conducted in healthy subjects who could not fully reflect the clinical situation, some lacked complete model assessments, and only a few were conducted in paediatric patients. This study explored the PPK characteristics of MHD in Chinese epileptic children, investigated the influence of patients’ demographic factors, biological factors and medication information on MHD PK, and confirmed WT as a significant covariate for the CL/F of MHD.…”

“…A one‐compartment model with first‐order elimination was selected as the basic structural model, corresponding to the previous studies . The typical population values of the PK parameters of the final model were as follows: TVCL = 3.25 L/h/70 kg, TVV = 151.41 L/70 kg, and Ka = 0.598 h −1 .…”

“…22 The differences in response to treatment may be caused by many factors, in addition to the variation in patient disease status, individual difference in drug disposition may also result in the failure of seizure treatments. The PPK approach enables the assess- Although several studies 1,2,9,12,13,20,23,24 have established OXC and MHD PPK models, some were conducted in healthy subjects who could not fully reflect the clinical situation, some lacked complete model assessments, and only a few 1,12,13,20,24 for CL and 1 for V. 25 In the study by Rodrigues et al, the median WT was fixed as the standard adult value of 70 kg, and four models were tested, including empirically estimating θ WT , fixing it to the above theoretical values, estimating it independently for children > 6 years and children < 6 years, and applying the body weight-dependent exponent model. 26 The estimated exponents for CL MHD /F and Vc MHD /F were 0.549 and 1.09, respectively.…”

Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children

“…This model allows a better understanding of MHD PK resulting from its formation from OXC and its elimination and takes into account the back-transformation of MHD into its parent compound. Previous population PK studies directly related OXC dose to MHD concentration, without considering OXC concentration [15][16][17][21][22][23][24]. Such an approach can be supported by the high bioavailability of OXC and the fact that OXC is almost completely converted into MHD.…”