Investigation Of Phenytoin And Warfarin Individualized Dosage Regimen Respectively Using NONMEM And Meta-analysis On The Basis Of Gene Target

Phenytoin, also known as Dilantin, is an effective antiepileptic drug for grand malepilepsy. Warfarin, an oral coumarin anticoagulant drug, is widely used in the treatmentof heart valve replacement surgery, deep vein thrombosis, pulmonary embolism, atrialfibrillation, etc. Both of them are characterized by the narrow therapeutic window andlarge inter-individual difference. Moreover, their plasma concentrations are susceptibleto a variety of different factors. Therefore, individualized medication according to thedifferent individual condition is desired particularly. This paper included two sections asfollow:Section1. Investigation of phenytoin individualized dosage program based on genetarget and NONMEMObjective: To set up a population pharmacokinetic model of phenytoin based on genetarget and NONMEM in order to provide reference for individual medication in clinicalpractice.Methods: Serum concentrations of phenytoin, genotypes of CYP2C9and CYP2C19andrelated clinical dates were collected from112patients who took phenytoin orally afterresection of intracranial neoplasms. The NONMEM software was used to getpopulation pharmacokinetic parameter, to set up a population pharmacokinetic finalmodel and to assess the model in clinical practice. Results: The population estimates of Vmaxand Kmwere23.8mg·h-1and5.84mg·L-1,respectively. The final model formula is:(1)when the genotype of CYP2C9is*1/*1andCYP2C19is*1/*1or*1/*2or*1/*3, Vmax=23.8×(WT/66.07)0.856×1.16(mg·h-1),Km=5.84×0.731(mg·L-1);(2) when the genotype of CYP2C9is*1/*1and CYP2C19is*2/*2or*2/*3or*3/*3, Vmax=23.8×(WT/66.07)0.856×0.874(mg·h-1), Km=5.84×0.659(mg·L-1);(3) when the genotype of CYP2C9is*1/*3and CYP2C19*1/*1or*1/*2or*1/*3or*2/*2or*2/*3or*3/*3, Vmax=23.8×(WT/66.07)0.856×0.796(mg·h-1),Km=5.84×0.291(mg·L-1). The population pharmacokinetic model was validated to beeffective and stable by bootstrap method. In the clinical applications, the plasmaconcentrations of phenytoin of9patients on day8reached effective therapeutic level(10~20mg·L-1).Conclusions: The final population pharmacokinetic model of phenytoin in patients afterresection of intracranial neoplasms can be established based on gene target andNONMEM, which can provide reference for clinical personalized medication ofphenytoin. Section2. Investigation of warfarin individual dosage based on gene target usingmeta-analysis methodObjective: To investigate the quantitive results of the effects of different genotypiccombination of CYP2C9and VKORC1-1639G>A on mean daily warfarin dose (MDWD)in order to provide reference for clinically personalized medication. Methods: Related databases including CNKI, CBM, WanFang Database and PubMed(2004.1-2013.7) were searched on computer. Literatures were screened and evaluatedaccording to the inclusion criteria. Meta-analyses were performed using RevMan5.1and Stata12.0software.Results: A total of9articles including3Chinese and6English were acquired.Compared with*1/*1+AA group, the MDWD in*1/*1+GG group,*1/*1+GA groupand*1/*3+GA group were increased by1.01(95%CI:0.38,1.65, P=0.002),0.41(95%CI:0.15,0.68, P=0.002) and0.06(95%CI:－0.06,0.18, P=0.31), respectively; MDWD in*1/*3+AA group and*3/*3+AA group decreased by0.29(95%CI:－0.45,－0.13,P=0.0004) and0.38(95%CI:－0.59,－0.17, P=0.0003), respectively. The sensitiveanalysis showed that the analysis results were stable.Conclusion: The meta-analysis presented the quantitive results of the effects of variousgenotypic combination of CYP2C9and VKORC1-1639G＞A on MDWD, which can beprovided references for warfarin personalized medicine.