Phenytoin dosage adjustment in Saudi epileptics: utilization of steady‐state pharmacokinetic parameters

Abstract

We determined the Michaelis-Menten parameters (Vmax and Km) in 271 Saudi epileptic patients having generalized tonic-clonic seizures and who were treated with phenytoin (PHT) using high pressure liquid chromatography (HPLC). The patients comprised 150 (55.4%) males and 121 (44.6%) females, with a mean age of 31.7 years (SD = 18.5). The mean Vmax for subjects less than 16 years of age was 10.35 mg/kg/day (SD = 0.73, range = 3.77-17.01), while for those above 16 years, the mean value was 7.99 mg/kg/day (SD = 0.15, range = 3.68-15.95). The difference was statistically significant (P < 0.001). Vmax was positively correlated with weight (r = 0.953), but negative with age (r = -0.903). Km values ranged from 1.01-20.87 mg/litre. The adult Km mean of 6.52 mg/l (SD = 0.24) was significantly higher than the mean of 4.79 mg/l (SD = 0.40) for pediatric patients (P < 0.01), but Km was correlated neither with age nor with weight. Our results showed no difference between the predicted and observed serum PHT concentrations in both the pediatric and adult patients when the respective age group Km and Vmax values were used to adjust PHT doses. The pediatric cases, however, required 30% more PHT per kilogram of body weight than the adults for the achievement of similar serum concentrations.

Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling

“…This is a general limitation for other published phenytoin models (e.g., [24,51,53]). Moreover, phenytoin clearance was described by Michaelis-Menten kinetics in our model, which is consistent with capacity-limiting metabolism at therapeutic concentrations of phenytoin [4,6] demonstrated in the literature (e.g., [44,49,50,54,55]). The only exception to our knowledge is Hennig et al [24] who used a linear elimination model in critically ill children, possibly because of increased Km values in their patients with head trauma [56].…”

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

“…To individualize a phenytoin dosage regimen, it is important to know certain pharmacokinetic parameters of phenytoin, including the maximum rate of metabolism (Vmax) and the Michaelis-Menten constant (Km). High variability in the values of Vmax and Km has been reported among populations [3][4][5][6][7][8][9][10]. Several factors have been identified to impact the variability of these parameters, including age, sex, weight, serum albumin, and drugs that either induce or inhibit the activity of the enzyme CYP2C9 [3][4][5][6][7][8][9][10].…”

“…High variability in the values of Vmax and Km has been reported among populations [3][4][5][6][7][8][9][10]. Several factors have been identified to impact the variability of these parameters, including age, sex, weight, serum albumin, and drugs that either induce or inhibit the activity of the enzyme CYP2C9 [3][4][5][6][7][8][9][10]. However, the values of Vmax and Km, as well as any factors influencing them, have never been studied in a population of Thai children.…”

“…The pharmacokinetics of phenytoin show high interindividual variability [3][4][5][6][7][8][9][10]; therefore individualizing a patient dosage regimen to obtain optimal plasma concentrations is crucial. Knowing the pharmacokinetic parameters of phenytoin, specifically, Vmax and Km, is important for optimizing phenytoin dosing.…”

“…Compared between age groups, the Vmax in the the 1 mo-6 y group of patients was significantly higher than in the 7-15 y group (14.65 vs. 8.21 mg/kg/d, respectively). Significant differences in Vmax between age groups can be attributed to increased activity by CYP2C9, an enzyme responsible for the metabolism of phenytoin primarily in younger children compared to adolescents [10,17].…”