Use of routine data for determination of the population pharmacokinetics and enteral biovailability of phenytoin in neonates and infants with seizures

Objective: To investigate the population pharmacokinetics and the enteral bioavailability of phenytoin in neonates and infants with seizures. Methods: Data (5 mg kg-1 day-1) from 83 patients were obtained retrospectively from the medical records following written ethical approval. A one-compartment model was fitted to the data using NONMEM with FOCE-interaction. Between-subject variability (BSV) and interoccasion variability (IOV) were modelled exponentially together with a log transform-both-sides exponential residual unexplained variance (RUV) model. Covariates in nested models were screened for significance (X2, 1, 0.01). Model validity was determined by bootstrapping with replacement (N=500 samples) from the dataset. Results: The parameters of final pharmacokinetic were: Clearance (L h-1) = 0.826.(current Weight [kg]/70)0.75.(1+0.0692.(Postnatal age [days]-11)); Volume of distribution (L) = 74.2.(current Weight [kg]/70); Enteral bioavailability = 0.76; Absorption rate constant (h-1) = 0.167. BSV for clearance and volume of distribution were 74.2% and 65.6%, respectively. The IOV in clearance was 54.4%. The RUV was 51.1%. Final model parameters deviated from mean bootstrap estimates by