Factors Influencing the Population Pharmacokinetic Parameters of Phenytoin in Adult Epileptic Patients in South Africa

Abstract

The influence of various covariates (including weight, race, smoking, gender, age, mild-to-moderate alcohol intake, and body surface area) on the population pharmacokinetic parameters of phenytoin in adult epileptic patients in South Africa was investigated. The parameters were the maximum metabolic rate (Vm) and the Michaelis-Menten (MM) constant (Km) of phenytoin. The study population comprised 332 black and colored epileptic patients (note: "black" refers to indigenous people of South Africa, who speak one of the Bantu languages as their native language; "colored" refers to people considered to be of mixed race, classified as such by the apartheid former government of South Africa). The influence of covariates on Vm and Km estimates was determined using nonlinear mixed-effects modeling (NONMEM). Parameter models describing the factors that could potentially influence Vm and Km were tested using the Michaelis-Menten parallel MM and first-order elimination models, to which 853 steady state dose-to-serum concentration pairs were fitted. The results indicated that body weight, smoking, race, and age (65 years or older), in descending order of importance, significantly influenced Vm (p < 0.05). Although a significant difference (p = 0.03) in Km was found between black and colored patients, incorporating the influence of race in Km in the final regression model did not improve the fit of the model to the data, which indicated that the variability in Km was accounted for by Vm. The scaling factors for smoking, colored patients and age (65 years or older) in Vm were 1.16, 1.10, and 0.88, respectively. These factors should be taken into account when adjusting phenytoin dose.

Phenytoin half-life and clearance during maintenance therapy in adults and elderly patients with epilepsy

“…In contrast, other studies have failed to find a significant age effect on PHT pharmacokinetics. 10,[21][22][23][24] The conflicting reports regarding an age effect on PHT pharmacokinetics may be due to several reasons. 5 Most other investigations assumed that plasma concentrations were measured under steady-state conditions and PHT bioavailability was similar across age groups.…”

“…[6][7][8][9][10] One approach to studying steady-state PHT pharmacokinetics that addresses some of these limitations is the use of a nonradioactive, stable-labeled (SL) isotope that can be administered parenterally while the patient remains on his or her oral drug regimen. 11 The SL isotope and regular PHT can be measured separately, allowing rigorous characterization of PHT pharmacokinetics while maintaining steady-state conditions.…”

“…SL-PHT was synthesized as a [2-13 C-1,3-15 N 2 ]-5,5-diphenylhydantoin sodium salt (MassTrace Inc., Woburn, MA) with a mass weight 3 units heavier (3ϩPHT) than unlabeled PHT found in commercial formulations. The SL-FOS was synthesized as [2,4,[5][6][7][8][9][10][11][12][13] C-1,3-15 N 2 ]-5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4-imidazolidinedione disodium salt (Isotech, Inc.). The 13 C and 15 N atoms were incorporated into the PHT component (5ϩPHT) of FOS resulting in a molecular weight 5 mass units greater than the PHT found in commercial formulations.…”

Developing a Nomogram for Dose Individualization of Phenytoin in Asian Pediatric Patients Derived From Population Pharmacokinetic Modeling of Saturable Pharmacokinetic Profiles of the Drug

“…33,34 Although we were unable to retrieve information on our patients' social history from the case files, it is unlikely that these factors would be of significance as our target population is in the pediatric age range and of conservative Asian culture. 33,34 Although we were unable to retrieve information on our patients' social history from the case files, it is unlikely that these factors would be of significance as our target population is in the pediatric age range and of conservative Asian culture.…”

The ‘apparent clearance’ of free phenytoin in elderly vs. younger adults

“…Studies of total plasma concentrations (i.e. drug bound to plasma protein plus unbound drug) have found a reduction [4][5][6][7], no change [8][9][10][11][12][13] and paradoxically an increase [14,15] in metabolic elimination in patients older than 65 years. These conflicting results have been attributed to methodological differences in how phenytoin metabolic elimination has been determined [1].…”