Title:Population Pharmacokinetics of Phenytoin Based on NONMEM in Patients with Intracranial Tumor During the First Week of Post-Craniotomy
VOLUME: 17 ISSUE: 7
Author(s):Zhong-dong Li, Meng Liu, Liang Li, Jing-hai Wan, Zhaojin Lei and Yong-an Huang
Affiliation:Department of Pharmacology, General Hospital of Air Force, PLA, No. 30 Fucheng Road, Beijing 100142, China.
Keywords:Cytochrome P450 2C9, NONMEM, pharmacokinetics, phenytoin, population.
Abstract:Background: It was reported that phenytoin can prevent early post traumatic seizures.
The present study aims to establish a population pharmacokinetic (PPK) model of oral phenytoin
in patients with intracranial tumor during the early periods, the first week, of post-craniotomy to
optimize phenytoin dosage regimen.
Methods: Sixty-two patients with intracranial tumor were genotyped for CYP2C9 and CYP2C19
by real time PCR (TaqMan probe), and subsequently their phenytoin dosage regimens were designed
according to the results of previous literature. A total of 123 plasma concentrations of oral
phenytoin during the early periods of post-craniotomy, patient demographics, clinical biochemical
indicators and drug combination were collected. A PPK model was performed using the nonlinear
mixed effects model (NONMEM) program.
Results: The final PPK model equations of oral phenytoin were found to be as follows: for patients
with CYP2C9 *1/*1, Vmax=22.66(BWT/60.96)0.454(mg/h) and Km =4.03 (mg/L); for patients
with CYP2C9*1/*3, Vmax = 16.65(BWT / 60.96 )0.454 (mg/h) and Km =5.96 (mg/L). The PPK model was proved
to be stable and effective by bootstrap method. Clinical individualized dosage regimens of additional 50 patients were
designed by above PPK model. Concentrations on the morning of Day 7 (D7 concentrations) of 56% (28/50) of these
patients were within the therapeutic range (1020mg/L), which demonstrated better improvement than that of 37.1%
of above 62 patients.
Conclusion: The final PPK model of oral phenytoin may be helpful to design phenytoin individualized dosage regimen
at the early stage of post-craniotomy when characteristics of patients meet these of subpopulation in the study.
