Validation of Population Pharmacokinetic Parameters of Phenytoin Using the Parallel Michaelis-Menten and First-Order Elimination Model

Abstract

This study was conducted to assess whether the parallel Michaelis-Menten and first-order elimination (MM+FO) model fitted the data better than the Michaelis-Menten (MM) model, and to validate the MM+FO model and its parameter estimates. The models were fitted to 853 steady state dose: serum concentration pairs obtained in 332 adults with epilepsy using nonlinear mixed-effects modeling (NONMEM). The MM+FO model fitted the data better than the MM model. The validity of the pharmacokinetic models and the estimated population parameter values was tested using the naive prediction method. The estimation and validation of the pharmacokinetic parameters were undertaken in two separate patient groups (cross-validation) obtained by splitting the data set. Patients were randomly allocated to two equally matched groups (groups 1 and 2). The predictive performance was assessed using 770 paired predicted versus actual dose or measured serum concentrations. The population pharmacokinetic parameters estimated by NONMEM in group 1 were validated in group 2 and vice versa. When predicting steady state serum concentration, the MM+FO model was clearly superior to the MM model (mean bias of 0.91 and 8.13 mg/L, respectively).

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine

“…Based on a review of literature and given the sparse nature of total phenytoin data, a 1-compartment PK model with first-order absorption and nonlinear clearance was evaluated using the ADVAN13 subroutine 22–28 . (22-28) Based on a published population PK model 23 (23), two types of kinetics were tested to describe the nonlinear clearance of phenytoin: 1) Michaelis-Menten kinetics or 2) first-order kinetics in parallel with Michaelis-Menten kinetics. Bioavailability for oral phenytoin after immediate release and extended-release formulations were assumed to be identical, and the parameter was fixed using published data 29 .…”

The role of heat-not-burn, snus and other nicotine-containing products as interventions for epileptic patients who take phenytoin and smoke cigarettes

“…Cigarette smoke had the highest impact relative to the patient factors (race, age, gender, mild-to-moderate alcohol intake, body surface area) that were studied, excluding weight on metabolic rate of phenytoin. The results indicated that smoke significantly influenced Vm (p < 0,05) [3] , [7] . In this population 49,7% of patients smoked cigarettes.…”

Evaluation of Fosphenytoin Therapeutic Drug Monitoring in the Neurocritical Care Unit

“…Phenytoin and the prodrug fosphenytoin are frequently used in the treatment of critically ill patients experiencing seizures or as prophylaxis in neurologically injured patients [1][2][3]. Phenytoin exhibits nonlinear elimination pharmacokinetics and has been known to have high interpatient dosing variability, with therapeutic drug monitoring being the standard of care in patients receiving either agent [4][5][6]. The volume of distribution (V d ) of phenytoin is estimated as approximately 0.7-1.0 L/kg but may be routinely unpredictable as it increases with both dose and rate, resulting in heightened difficulty when trying to use pharmacokinetic models to predict drug concentrations [3,7,8].…”