Determination of Pharmacokinetic Parameters and Factors Influencing the Pharmacokinetic Parameters of Phenytoin in Thai Children With Epilepsy

Abstract

Objective: Phenytoin displays nonlinear pharmacokinetics due to the saturation of its’ metabolizing enzymes, thus making dosing adjustments a challenge in clinical practice. However, data on the pharmacokinetic parameters of phenytoin in pediatric patients with epilepsy in Thailand remain lacking. This study aimed to determine the pharmacokinetic parameters of phenytoin, and the factors influencing them in epileptic Thai children using therapeutic drug monitoring data.
 Methods: Steady state phenytoin plasma concentrations were collected from 96 Thai children with epilepsy aged ≤ 15 y. For individuals having a single steady-state concentration (Css) on one dosage, the Vmax was determined by fixing Km = 4.5 mg/l. For patients with two values for Css with different dosages, the Ludden method was used to determine Vmax and Km. Influences on Vmax and Km by demographic factors including age, sex, weight, serum albumin, and the use of CYP2C9 inducers (carbamazepine, phenobarbital, folic acid, and vigabatrin) and inhibitors (valproic acid and topiramate) were determined by linear mixed-effects regression.
 Results: The majority of patients had sub-therapeutic plasma concentrations of phenytoin. The Vmax and Km were estimated to be 9.84 mg/kg/d and 2.32 mg/l, respectively. Age and weight significantly influenced Vmax, whereas Km had no significant influencing factors.
 Conclusion: The Vmax estimated in this study is different from other populations previously reported. Our results suggest that increased phenytoin dosages may be required to achieve optimal concentrations due to the sub-therapeutic concentrations reported here. The results from this study are beneficial for phenytoin dosage individualization in Thai children.

An analysis of the Michaelis-Menten pharmacokinetics of phenytoin in epileptic Indonesian adults

“…The The values of Vmax and Km obtained in this study have followed those found by other researchers (Ismail & Rahman, 1990;Suzuki et al, 1994;Chanruang et al, 2021). Like other researchers, this study also found large inter-subject variability in the values of Vmax and Km.…”

“…Several literature reviews showed that the variability between individual Michaelis-Menten pharmacokinetic parameters Vmax and Km is quite large. They concluded that genetic differences and the effect of pharmacokinetic saturation of phenytoin are more essential factors in determining steady serum phenytoin levels than other factors such as age, weight, height, and gender (Ismail & Rahman, 1990;Suzuki et al, 1994;Chanruang et al, 2021).…”