Population Pharmacokinetics Of Phenytoin In Patients After Intracranial Tumorectomy And System Evaluation Of The Effect Of Antiepileptic Drug Regimen Including Phenytoin On Bone Mineral Density Of Patients With Epilepsy

Phenytoin (Dilantin) is an effective antiepileptic drug, which has been alsosuccessful used to treat arrhythmia and neuropathic pain. However, phenytoin ischaracterized by the narrow therapeutic window, larger interindividual,andintraindividual variability of pharmacokinetic process and relatively serious adversereactions in central nervous system and abnormality of bone metabolism. Therefore,individualized medication according to the different individual condition is desired.This paper had the following two parts:Part1. Population pharmacokinetics of phenytoin in patients after intracranialtumorectomyObjective: To set up a population pharmacokinetic model of phenytoin based onNONMEM for individual medication in clinical practice.Methods: Serum concentrations of phenytoin, genotype of CYP2C9and CYP2C19andrelated clinical dates were collected from62patients who took orally phenytoin afterresection of intracranial neoplasms. The NONMEM software was used to getpopulation pharmacokinetic parameter, to set up a final model, and to assess the modelin clinical practice.Results: The population estimates of Vmax and Km were19.2mg/h and6.18mg/L,respectively. The final model formula is:(1) when the genotype of CYP2C9is*1/*1,Vmax=19.2×(WT/60.96)0.454×1.18(mg/h)，Km=6.18×0.652(mg/L);(2) when the genotype of CYP2C9is*1/*3, Vmax=19.2×(WT/60.96)0.454×0.867(mg/h)，Km=6.18×0.965(mg/L). The population pharmacokinetic model was validated to beeffective and stable by bootstrap methd. In the clinical applications, The plasmaconcentrations of phenytoin of9patients out of10on day7reached effectivetherapeutic level.Conclusions: The population pharmacokinetic final model of phenytoin in patients afterresection of intracranial neoplasms can be established using NONMEM software, whichcan be applied in clinical practice. Part2. A system evaluation of the effect of antiepileptic drug regimen includingphenytoin on bone mineral density of patients with epilepsyObjective: To determine the effect of antiepileptic drugs(AEDs) including phenytoin onthe bone mineral density (BMD) and bone metabolism.Methods: The Pubmed, CNKI and CBM (finished on March2013) were searchedelectronically using antiepileptic drugs (AEDs), bone mineral density and bonemetabolism as keywords. Meta analysis was performed by RevMan5and Stata12.0software. Heterogeneity was examined by Chi-square test. Fixed effects model orrandom effects model was used to pool the data. Sensitivity analyses and Metaregression were conducted to verify the robustness of the results.Results: A total of9papers involving in12303patients were identified. Compared tocontrol group, lumbar BMD and25-hydroxyvitaminD of patients in the experimentalgroup with antiepileptic drugs including phenytoin was decreased by0.90（95%CI:-1.73，0.08，P=0.03）and0.48(95%CI-0.67，-0.030，P<0.00001). But the alkalinephosphatase increased by0.73（95%CI:0.4，1.05，P<0.00001）.The sources of heterogeneity in femur neck and lumbar were found to be the study of Stephen et al(P<0.00001) and sample size (P=0.03), respectively.Conclusion: For patients treated by long-term antiepileptic drugs including phenytoin,it is required to monitor the alteration of their lumbar BMD, blood25-hydroxyvitaminD and alkaline phosphatase regularly.