AI Article Synopsis
- The study focused on creating a population pharmacokinetic (PPK) model for 10-monohydroxy derivative (MHD), the active metabolite of the antiepileptic drug oxcarbazepine, in Chinese children with epilepsy, to better understand how genetic variations affect drug metabolism.
- Data from 141 pediatric patients was collected, assessing various factors like body weight, gender, and genotype for specific enzymes, aiming to see how these influenced MHD pharmacokinetics.
- The findings revealed that body weight significantly impacted MHD clearance, while genetic factors showed no notable effect; a new dosing strategy was proposed to personalize oxcarbazepine treatment based on individual characteristics.
Article Abstract
Purpose: Oxcarbazepine (OXC) is an antiepileptic drug metabolised to active 10-monohydroxy derivative (MHD) following oral administration. There are no MHD population pharmacokinetic (PPK) models that describe the influence of genetic factors on MHD pharmacokinetics (PK). We developed a PPK model of MHD to investigate gene polymorphism of enzymes associated with MHD PK in Chinese paediatric epilepsy patients and evaluated its utility for dose individualisation.
Methods: Data were prospectively collected from 141 paediatric epilepsy patients (aged ≤ 14 years) who received OXC therapy at the First Affiliated Hospital of Fujian Medical University. The trough concentrations at steady state were determined by enzyme-multiplied immunoassay. Patients were genotyped for four single nucleotide polymorphisms (UGT2B7 802T>C, UGT1A9 I399C>T, ABCB1 3435C>T, and ABCB2 1249G>A). Patient gender, age, body weight (BW), hepatorenal function, and co-administrations were recorded. The PPK model was developed using nonlinear mixed-effects modelling software. The clinical performance of the final model was evaluated by including additional paediatric patients (n = 20) in the validation group.
Results: Oral clearance of MHD was significantly influenced by BW. The MHD PK was unrelated to the other covariates, such as the four single nucleotide polymorphisms and co-administration with new-generation antiepileptic drugs. The final BW-dependent exponent model showed the best fit with our data and predicted the trough concentrations in the validation group more accurately than the basic model. A new dosing strategy combining the dosage guideline and Bayesian method is proposed to individualise OXC regimens.
Conclusion: A PPK model was established to estimate individual MHD clearance in paediatric patients taking OXC to develop individualised OXC dosing regimens for Chinese paediatric epilepsy patients.
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| http://dx.doi.org/10.1007/s00228-018-2600-8 | DOI Listing |
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