基于CYP3A表型和基因型的环孢素个体化用药研究
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摘要
目的本研究拟构建肾移植患者的环孢素稳态浓度和稳定剂量预测模型。方法通过回归法和随机森林法建立环孢素药动学预测模型。结果得到回归模型为:C/D=4.025-0.056*HOM-0.018*Height+0.012*AST,决定系数R2为0.405。随机森林模型中,拟合系数(R2~)和预测系数(Q~2)分别为0.94 and 0.68。结论首次在肾移植患者中建立基于CYP3A表型,CYP3A5基因型和其它影响因素的环孢素药动学预测模型。
OBJECTIVE The present study may provide a new idea for personalized medicine of immunosuppressants.METHODS Establishing a model to predict cyclosporine trough concentrations and dosages based on regression analysis and random forest.RESULTS The regression equation was as follows,the coefficient was 0.405:C/D=4.025-0.056*HOM-0.018* Height +0.012*AST.Random forest models provided high goodness of fit(R2) and high predictability(Q2) with 0.94 and 0.68.CONCLUSIONS A novel computational model,incorporating an endogenous CYP3 A4 phenotype,CYP3 A5*3 genotype and other clinical determinants of cyclosporine exposure is first developed.
OBJECTIVE The present study may provide a new idea for personalized medicine of immunosuppressants.METHODS Establishing a model to predict cyclosporine trough concentrations and dosages based on regression analysis and random forest.RESULTS The regression equation was as follows,the coefficient was 0.405:C/D=4.025-0.056*HOM-0.018* Height +0.012*AST.Random forest models provided high goodness of fit(R2) and high predictability(Q2) with 0.94 and 0.68.CONCLUSIONS A novel computational model,incorporating an endogenous CYP3 A4 phenotype,CYP3 A5*3 genotype and other clinical determinants of cyclosporine exposure is first developed.
引文
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[5]Barnard,J.B.,Richardson,S.,Sheldon,S.,Fildes,J.,Pravica,V.,Hutchinson,I.V.,et al.The MDR1/ABCB1 gene,a high-impact risk factor for cardiac transplant rejection[J].Transplantation:2006,82(12):1677-1682.
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[7]Burckart,G.J.,& Liu,X.I.Pharmacogenetics in transplant patients:can it predict pharmacokinetics and pharmacodynamics?[J]Ther Drug Monit:2006,28(1):23-30.
[8]Burckart,G.J.,Hutchinson,I.V.,& Zeevi,A.Pharmacogenomics and lung transplantation:clinical implications[J].Pharmacogenomics J:2006,6(5):301-10.
[9]Cattaneo,D.,Baldelli,S.,& Perico,N.Pharmacogenetics of immunosuppressants:progress,pitfalls and promises[J].Am J Transplant:2008,8(7):1374-83.
[10]Thervet,E.,Anglicheau,D.,Legendre,C.,& Beaune,P.Role of pharmacogenetics of immunosuppressive drugs in organ transplantation[J].Ther Drug Monit:2008,30(2):143-50.
[2]Dunn CJ,Wagstaff AJ,Perry CM,et al.Cyclosporin:an updated review of the pharmacokinetic properties,clinical efficacy and tolerability of a microemulsion-based formulation (neoral)1 in organ transplantation[J].Drugs:2001,61(13):1957-2016.
[3]Albrecht W,Storck M,Pfetsch E,et al.Development and application of a high-performance liquid chromatography-based assay for determination of the activity of inosine 5-monophos-phate dehydrogenase in whole blood and isolated mononuclear cells[J].Ther Drug Monit:2000,22(3):283-294.
[4]Wallemacq PE,Verbeeck RK.Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients[J].Clin Pharmacokinet:2001,40(4):283-295.
[5]Barnard,J.B.,Richardson,S.,Sheldon,S.,Fildes,J.,Pravica,V.,Hutchinson,I.V.,et al.The MDR1/ABCB1 gene,a high-impact risk factor for cardiac transplant rejection[J].Transplantation:2006,82(12):1677-1682.
[6]Van Hooff JP,Boots JM,van Duijnhoven EM,et al.Dosing and management guidelines for tacrolimus in renal transplant patients[J].Transplant Proc:1999,31(7A):54S-57S.
[7]Burckart,G.J.,& Liu,X.I.Pharmacogenetics in transplant patients:can it predict pharmacokinetics and pharmacodynamics?[J]Ther Drug Monit:2006,28(1):23-30.
[8]Burckart,G.J.,Hutchinson,I.V.,& Zeevi,A.Pharmacogenomics and lung transplantation:clinical implications[J].Pharmacogenomics J:2006,6(5):301-10.
[9]Cattaneo,D.,Baldelli,S.,& Perico,N.Pharmacogenetics of immunosuppressants:progress,pitfalls and promises[J].Am J Transplant:2008,8(7):1374-83.
[10]Thervet,E.,Anglicheau,D.,Legendre,C.,& Beaune,P.Role of pharmacogenetics of immunosuppressive drugs in organ transplantation[J].Ther Drug Monit:2008,30(2):143-50.