The Effects of CYP3A5 Genetic Polymorphisms on Serum Tacrolimus Dose-Adjusted Concentrations and Long-Term Prognosis in Chinese Heart Transplantation Recipients

Background and Objectives Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of cytochrome P450 (CYP) 3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C...

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Published in	European journal of drug metabolism and pharmacokinetics Vol. 44; no. 6; pp. 771 - 776
Main Authors	Liu, Bing-yang, Chen, Wen-qian, Chen, Zhi-gao, Huang, Jie, Liao, Zhong-kai, Liu, Qing, Zheng, Zhe, Song, Yun-hu, Wang, Wei, Hu, Sheng-shou
Format	Journal Article
Language	English
Published	Cham Springer International Publishing 01.12.2019
Subjects	Adult Asian Continental Ancestry Group Biomedical and Life Sciences Biomedicine Cytochrome P-450 CYP3A - genetics Female Genotype Heart Transplantation Human Physiology Humans Immunosuppressive Agents - administration & dosage Immunosuppressive Agents - blood Kaplan-Meier Estimate Male Medical Biochemistry Middle Aged Original Research Article Pharmaceutical Sciences/Technology Pharmacology/Toxicology Pharmacy Polymorphism, Single Nucleotide Prognosis Tacrolimus - administration & dosage Tacrolimus - blood
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Abstract	Background and Objectives Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of cytochrome P450 (CYP) 3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients. Methods We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36 months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6 months after heart transplantion to evaluate acute rejection degrees. All participants were then followed up annually until May 2018. The designed primary endpoint was all-cause mortality. Results In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A53/3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A51/3, n = 15) at all time points ( P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6 months after heart transplantion. The median follow-up period was 94.7 months, and eight patients died. Kaplan–Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314). Conclusions CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors.
AbstractList	Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of cytochrome P450 (CYP) 3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients.BACKGROUND AND OBJECTIVESEffective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of cytochrome P450 (CYP) 3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients.We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36 months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6 months after heart transplantion to evaluate acute rejection degrees. All participants were then followed up annually until May 2018. The designed primary endpoint was all-cause mortality.METHODSWe detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36 months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6 months after heart transplantion to evaluate acute rejection degrees. All participants were then followed up annually until May 2018. The designed primary endpoint was all-cause mortality.In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A53/3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A51/3, n = 15) at all time points (P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6 months after heart transplantion. The median follow-up period was 94.7 months, and eight patients died. Kaplan-Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314).RESULTSIn 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A53/3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A51/3, n = 15) at all time points (P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6 months after heart transplantion. The median follow-up period was 94.7 months, and eight patients died. Kaplan-Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314).CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors.CONCLUSIONSCYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors. Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of cytochrome P450 (CYP) 3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients. We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36 months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6 months after heart transplantion to evaluate acute rejection degrees. All participants were then followed up annually until May 2018. The designed primary endpoint was all-cause mortality. In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A53/3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A51/3, n = 15) at all time points (P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6 months after heart transplantion. The median follow-up period was 94.7 months, and eight patients died. Kaplan-Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314). CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors. Background and Objectives Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of cytochrome P450 (CYP) 3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients. Methods We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36 months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6 months after heart transplantion to evaluate acute rejection degrees. All participants were then followed up annually until May 2018. The designed primary endpoint was all-cause mortality. Results In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A53/3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A51/3, n = 15) at all time points ( P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6 months after heart transplantion. The median follow-up period was 94.7 months, and eight patients died. Kaplan–Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314). Conclusions CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors.
Author	Zheng, Zhe Liu, Bing-yang Wang, Wei Hu, Sheng-shou Liao, Zhong-kai Song, Yun-hu Huang, Jie Liu, Qing Chen, Wen-qian Chen, Zhi-gao
Author_xml	– sequence: 1 givenname: Bing-yang surname: Liu fullname: Liu, Bing-yang organization: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College – sequence: 2 givenname: Wen-qian surname: Chen fullname: Chen, Wen-qian organization: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College – sequence: 3 givenname: Zhi-gao surname: Chen fullname: Chen, Zhi-gao organization: Fuwai Central China Cardiovascular Hospital – sequence: 4 givenname: Jie surname: Huang fullname: Huang, Jie email: huangjie@fuwai.com organization: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College – sequence: 5 givenname: Zhong-kai surname: Liao fullname: Liao, Zhong-kai organization: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College – sequence: 6 givenname: Qing surname: Liu fullname: Liu, Qing organization: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College – sequence: 7 givenname: Zhe surname: Zheng fullname: Zheng, Zhe organization: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College – sequence: 8 givenname: Yun-hu surname: Song fullname: Song, Yun-hu organization: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College – sequence: 9 givenname: Wei surname: Wang fullname: Wang, Wei organization: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College – sequence: 10 givenname: Sheng-shou surname: Hu fullname: Hu, Sheng-shou organization: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College
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Cites_doi	10.1038/clpt.1993.132 10.1097/FTD.0000000000000080 10.2165/00003088-200443100-00001 10.1111/ajt.13788 10.1038/86882 10.1016/j.transproceed.2012.09.062 10.2217/pgs-2016-0146 10.1111/ctr.12790 10.1016/j.healun.2011.08.004 10.1111/j.1399-0012.2009.01198.x 10.1111/j.1399-0012.2005.00370.x 10.1038/sj.clpt.6100039 10.1093/ndt/gfr253 10.1373/clinchem.2005.050047 10.1097/FPC.0b013e32834a48ca 10.1016/j.healun.2011.08.001 10.1016/S0149-2918(02)85038-X 10.1016/j.healun.2005.03.019 10.1016/j.transproceed.2010.08.063 10.1111/j.1432-2277.2012.01446.x
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Snippet	Background and Objectives Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to... Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of... Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of...
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SubjectTerms	Adult Asian Continental Ancestry Group Biomedical and Life Sciences Biomedicine Cytochrome P-450 CYP3A - genetics Female Genotype Heart Transplantation Human Physiology Humans Immunosuppressive Agents - administration & dosage Immunosuppressive Agents - blood Kaplan-Meier Estimate Male Medical Biochemistry Middle Aged Original Research Article Pharmaceutical Sciences/Technology Pharmacology/Toxicology Pharmacy Polymorphism, Single Nucleotide Prognosis Tacrolimus - administration & dosage Tacrolimus - blood
Title	The Effects of CYP3A5 Genetic Polymorphisms on Serum Tacrolimus Dose-Adjusted Concentrations and Long-Term Prognosis in Chinese Heart Transplantation Recipients
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