2006 - Brugge/Bruges - Belgium

PAGE 2006: Applications- CNS
MOHAMMED Al ZAABI

Use of Routine Data for Determination of the Population Pharmacokinetics and Enteral Bioavailability of Phenytoin in Neonates and Infants with Seizures

Al Za’abi MA (1), Xiaonian X (2), Donovan T (3), Charles BG (1)

(1) School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia; (2) Sino-German Research Institute, Nanchang, PR China; (3) Grantley Stable Neonatal Unit, Royal Women’s Hospital, Brisbane, Australia

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 <9%.

Conclusion: Phenytoin in young infants can be described by linear pharmacokinetics. Clearance and volume, allometrically scaled to 70 kg body size, were similar to adult values indicating there were was no biological differences between adults and infants for phenytoin disposition based on size alone. Postnatal age was a significant predictor for clearance in infants independent of body size. The results provide a basis for more rational prescribing of phenytoin in these patients.




Reference: PAGE 15 (2006) Abstr 950 [www.page-meeting.org/?abstract=950]
Poster: Applications- CNS
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