Background Mycophenolic acid （MPA） as an anti-proliferative immune-suppressive agent is used in the majority of immunosuppressive regimens in solid organ transplantation. This study aimed to investigate the pharmaco...Background Mycophenolic acid （MPA） as an anti-proliferative immune-suppressive agent is used in the majority of immunosuppressive regimens in solid organ transplantation. This study aimed to investigate the pharmacokinetic （PK） characteristics of enteric-coated mycophenolate sodium （EC-MPS） and area under the curve （AUC） from 0 to 12 hours with limited sampling strategies （LSSs） in Chinese renal transplant recipients. Methods This study was conducted in 10 Chinese renal transplant patients receiving living donor and treated with EC-MPS, cyclosporine, and corticosteroids. MPA concentrations were measured by enzyme multiplied immunoassay technique （EMIT）. Whole 12-hour PK profiles were obtained on Day 4 after operation. LSSs with jackknife technique, multiple stepwise regression analysis, and Bland-Altman analysis were developed to estimate MPAAUC. Results The mean maximum plasma concentration, the mean time for it to reach peak （Tmax）, and the mean MPA AUC were （11.38±2.49） mg/L, （4.85±3.32） hours, and （63.19±13.54） mg.h.L1, respectively. Among the 10 profiles, MPA AUC of four patients was significantly higher than that of the other six patients, and the corresponding Tmax was significantly longer than that of the other six patients. No patient exhibited a second peak caused by enterohepatic recirculation. The best models were as follows： 27.46＋0.94C3＋3.24C8＋2.81C10 （f2=0.972）, which was used to predict AUC of fast metabolizer with a mean prediction error （MPE） of -0.21% and a mean absolute prediction error （MAE） of 2.59%; 36.65＋3.08Ce＋5.30C10-4.04C12 （r2=0.992）, which was used to predict AUC of slow metabolizer with a MPE of 0.58% and a MAE of 1.95%. Conclusions The PKs of EC-MPS had a high variability among Chinese renal transplant recipients. The preliminary PK data indicated the existence of slow and fast metabolizer. These findings may be associated with the enterohepatic rec.irculation.展开更多
The aim of the research was to investigate the pharmacokinetics(PK) of enteric-coated mycophenolate sodium(EC-MPS) by quantification of the active metabolite of mycophenolic acid(MPA)after multiple escalating oral dos...The aim of the research was to investigate the pharmacokinetics(PK) of enteric-coated mycophenolate sodium(EC-MPS) by quantification of the active metabolite of mycophenolic acid(MPA)after multiple escalating oral doses in Han kidney transplant recipients. A total of 28 Han postoperative kidney transplant recipients were given a multiple-dose of 540, 720 or 900 mg of EC-MPS two times a day in combination with tacrolimus for 6 days. Blood specimens were collected at each time point from0 to 12 h after EC-MPS administration. MPA plasma concentrations were measured by UPLC–UV. The relationship between the EC-MPS dose and its PK parameters was assessed. In the range from 540 to900 mg, C_(max) and AUC_(0–12h) did not increase with dose escalation. The AUC_(0–12h), C_(max), C_0 and T_(max) for the 540 720 and 900 mg doses were not significantly different, respectively(P 40.05). AUC_0–12 h and C_(max) were increased less than proportionally with increasing EC-MPS dose levels. Inter-individual variability in AUC_(0–12h), C_(max) and C_0 were considerable. Nonlinear PK relationships were found from the doses of 540–900 mg of EC-MPS.展开更多
Mycophenolic acid, the active metabolite for mycophenolate mofetil and mycophenolic sodium, is a strong, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase, the key enzyme in de novo synthesis...Mycophenolic acid, the active metabolite for mycophenolate mofetil and mycophenolic sodium, is a strong, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase, the key enzyme in de novo synthesis of guanosine nucleotides leading to selective inhibition of lymphocyte proliferation. Mycophenolic acid has been evaluated as induction and remission maintenance agent in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Since the course of disease of AAV usually requires long term immunosuppression, mycophenolate has been explored as a less toxic agent compared to cyclophosphamide and azathioprine. Mycophenolate is a potent immunosuppressive agent in the therapy of AAV, non-inferior to other available drugs with comparable side effect profile. Therefore, it could be a valuable alternative in cases of toxicity with life threatening side effects or intolerance to cyclophosphamide or azathioprine, in cases with high cumulative dose of cyclophosphamide, but also in cases with insufficient response. Several studies have shown a higher relapse rate following discontinuation of mycophenolate or in mycophenolate treated subjects that raises concerns about its usefulness in the treatment of AAV. This review describes the efficacy of mycophenolate in AAV as remission induction agent, as remission maintenance agent, and as therapeutic option in relapsing AAV disease, the relapse rate following discontinuation of mycophenolate, and the adverse events related to mycophenolate treatment.展开更多
Background： lmmunosuppressive agents are still inefficient in preventing biopsy-proven acute rejection （BPAR） alter expanded criteria donor （ECD） kidney transplantation. The aim of this study was to investigate t...Background： lmmunosuppressive agents are still inefficient in preventing biopsy-proven acute rejection （BPAR） alter expanded criteria donor （ECD） kidney transplantation. The aim of this study was to investigate the relationships between early imrnunosuppressive exposure and the development of BPAR. Methods： We performed a retrospective study of 58 recipients of ECD kidney transplantation treated with enteric-coated-mycophenolate sodium, tacrolirnus （Tac）, and prednisone. The levels of mycophenolic acid-area under the curve （MPA-AUC）0-12h and Tac C0 were measured at the 1st week and the 1st month posttransplant, respectively. The correlation was assessed by multivariate logistic regression. Results： The occurrence rates of BPAR and antibody-mediated rejection were 24.1% and 10.3%, respectively. A low level of MPA-AUC0-12h at the 1st week posttransplant was found in BPAR recipients （38.42 ± 8.37 vs. 50.64 ± 13.22, P 〈 0.01）. In addition, the incidence of BPAR was significantly high （P 〈 0.05） when the MPA-AUC0-12h level was 〈30 mg·h-1·L-1 at the 1st week （ 15.0% vs. 44.4%） or the Tac C0 was 〈4 ng/ml at the 1 st month posttransplant （33.3% vs. 21.6%）. Multivariable logistic regression analysis showed that the MPA-AUC 0-12 h at the 1st week （OR： 0.842, 95% CI： 0.784-0.903） and the Tac C0 at the 1st month （OR： 0.904, 95% C7： 0.822-0.986） had significant inverse correlation with BPA R （ P 〈 0.05 ）. Conclusions： Low-level exposure of MPA and Tac C0 in the early weeks posttransplant reflects an increased acute rejection risk, which suggested that MPA-AUC0-12h 〈30 mg·h-1·L -1 and Tac C0 〈4 ng/ml should be avoided in the first few weeks alter transplantation.展开更多
目的:比较强化剂量与标准剂量霉酚酸类药物用于成年肾移植受者的有效性与安全性,为临床合理用药提供循证参考。方法:计算机检索Embase、PubMed、Cochrane图书馆、Clinical trials.gov、中国知识资源总库、万方数据、中国生物医学文献数...目的:比较强化剂量与标准剂量霉酚酸类药物用于成年肾移植受者的有效性与安全性,为临床合理用药提供循证参考。方法:计算机检索Embase、PubMed、Cochrane图书馆、Clinical trials.gov、中国知识资源总库、万方数据、中国生物医学文献数据库,检索时限均为各数据库建库起至2020年3月,收集霉酚酸类药物[吗替麦考酚酯(MMF)、麦考酚钠肠溶片(EC-MPS)]强化剂量对比标准剂量用于成年肾移植受者的随机对照试验(RCT)和队列研究;筛选文献、提取资料后,采用Cochrane干预措施系统评价手册(第5版)推荐的偏倚风险评估工具对RCT进行质量评价,采用NOS量表对队列研究进行质量评价;采用Rev Man 5.3软件进行Meta分析,并进行敏感性分析。结果:共纳入8项研究,其中6项为RCT、2项为队列研究,共1637例患者。Meta分析结果显示,强化剂量组患者经活检证实的急性排斥反应(BPAR)发生率[RR=0.65,95%CI(0.48,0.89),P=0.007]、巨细胞病毒(CMV)感染发生率[RR=0.39,95%CI(0.17,0.91),P=0.03]均显著低于对照组。按药物进行的亚组分析结果显示,MMF强化剂量组[RR=0.72,95%CI(0.53,0.99),P=0.04]、EC-MPS强化剂量组[RR=0.19,95%CI(0.04,0.81),P=0.03]患者的BPAR发生率均显著低于标准剂量组;MMF强化剂量组[RR=0.16,95%CI(0.02,1.33),P=0.09]、EC-MPS强化剂量组[RR=0.51,95%CI(0.20,1.30),P=0.16]患者的CMV感染发生率与标准剂量组比较,差异均无统计学意义(P>0.05)。两组患者排斥反应、治疗失败、移植物丢失、终止治疗、病死、总体不良事件、感染(总体)、BK病毒感染、尿路感染、血液系统不良事件(总体)、白细胞减少、贫血、血小板减少、胃肠道不良事件(总体)、恶心、呕吐、腹泻等发生率比较,差异均无统计学意义(P>0.05)。敏感性分析结果显示,排斥反应、CMV感染、白细胞减少发生率的结果稳定性一般。结论:早期强化剂量霉酚酸类药物用于成年肾移植受者的有效性、安全性与标准剂量总体相当,虽然强化剂量可降低BPAR及CMV感染的发生风险,但结合敏感性分析结果,建议应谨慎解读排斥反应、CMV感染、白细胞减少发生率等结果。展开更多
目的:观察肝移植术后早期麦考酚钠肠溶片(enteric-coated mycophenolate sodium,ECMPS)药代动力学特点.方法:25例肝移植受者术后联合应用他克莫司Tacrolimus(FK506)和EC-MPS治疗.ECMPS口服剂量为720 mg,2次/d.术后7、21 d分别在服药前...目的:观察肝移植术后早期麦考酚钠肠溶片(enteric-coated mycophenolate sodium,ECMPS)药代动力学特点.方法:25例肝移植受者术后联合应用他克莫司Tacrolimus(FK506)和EC-MPS治疗.ECMPS口服剂量为720 mg,2次/d.术后7、21 d分别在服药前及服药后1、1.5、2、2.5、3、4、6、8和12 h取外周血,采用高效液相色谱法(high performance liquid chromalography,H P L C)测定血浆麦考酚酸(m yc o p h e n o l i c acid,MPA)浓度.WinNonlin软件计算MPA药时曲线下面积(area of concentration-time under the curve,AUC).同时测定FK506谷浓度(FK506-C0 h)及肝、肾功能和血细胞记数.结果:合并43套数据,MPA-AUC0-12 h平均为40.36(μg·h)/mL±17.20(μg·h)/mL,Cmax为16.66μg/mL±9.73μg/mL,Tmax为3.14 h±1.78 h.MPA-C0 h-C12 h与MPA-AUC0-12 h的相关性不显著(r2<0.75).MPA-AUC0-12 h与FK506-C0 h、血清白蛋白水平及肌酐清除率显著相关性(P>0.05).结论:肝移植后早期患者服用EC-MPS MPAAUC0-12 h个体间差异很大;单个时间点MPA浓度不能有效反映MPA-AUC0-12 h;FK506-C0 h、血清白蛋白水平及肌酐清除率不影响MPAAUC0-12 h.展开更多
文摘Background Mycophenolic acid （MPA） as an anti-proliferative immune-suppressive agent is used in the majority of immunosuppressive regimens in solid organ transplantation. This study aimed to investigate the pharmacokinetic （PK） characteristics of enteric-coated mycophenolate sodium （EC-MPS） and area under the curve （AUC） from 0 to 12 hours with limited sampling strategies （LSSs） in Chinese renal transplant recipients. Methods This study was conducted in 10 Chinese renal transplant patients receiving living donor and treated with EC-MPS, cyclosporine, and corticosteroids. MPA concentrations were measured by enzyme multiplied immunoassay technique （EMIT）. Whole 12-hour PK profiles were obtained on Day 4 after operation. LSSs with jackknife technique, multiple stepwise regression analysis, and Bland-Altman analysis were developed to estimate MPAAUC. Results The mean maximum plasma concentration, the mean time for it to reach peak （Tmax）, and the mean MPA AUC were （11.38±2.49） mg/L, （4.85±3.32） hours, and （63.19±13.54） mg.h.L1, respectively. Among the 10 profiles, MPA AUC of four patients was significantly higher than that of the other six patients, and the corresponding Tmax was significantly longer than that of the other six patients. No patient exhibited a second peak caused by enterohepatic recirculation. The best models were as follows： 27.46＋0.94C3＋3.24C8＋2.81C10 （f2=0.972）, which was used to predict AUC of fast metabolizer with a mean prediction error （MPE） of -0.21% and a mean absolute prediction error （MAE） of 2.59%; 36.65＋3.08Ce＋5.30C10-4.04C12 （r2=0.992）, which was used to predict AUC of slow metabolizer with a MPE of 0.58% and a MAE of 1.95%. Conclusions The PKs of EC-MPS had a high variability among Chinese renal transplant recipients. The preliminary PK data indicated the existence of slow and fast metabolizer. These findings may be associated with the enterohepatic rec.irculation.
基金supported by the youth fund of The First Affiliated Hospital of Zhengzhou University
文摘The aim of the research was to investigate the pharmacokinetics(PK) of enteric-coated mycophenolate sodium(EC-MPS) by quantification of the active metabolite of mycophenolic acid(MPA)after multiple escalating oral doses in Han kidney transplant recipients. A total of 28 Han postoperative kidney transplant recipients were given a multiple-dose of 540, 720 or 900 mg of EC-MPS two times a day in combination with tacrolimus for 6 days. Blood specimens were collected at each time point from0 to 12 h after EC-MPS administration. MPA plasma concentrations were measured by UPLC–UV. The relationship between the EC-MPS dose and its PK parameters was assessed. In the range from 540 to900 mg, C_(max) and AUC_(0–12h) did not increase with dose escalation. The AUC_(0–12h), C_(max), C_0 and T_(max) for the 540 720 and 900 mg doses were not significantly different, respectively(P 40.05). AUC_0–12 h and C_(max) were increased less than proportionally with increasing EC-MPS dose levels. Inter-individual variability in AUC_(0–12h), C_(max) and C_0 were considerable. Nonlinear PK relationships were found from the doses of 540–900 mg of EC-MPS.
文摘Mycophenolic acid, the active metabolite for mycophenolate mofetil and mycophenolic sodium, is a strong, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase, the key enzyme in de novo synthesis of guanosine nucleotides leading to selective inhibition of lymphocyte proliferation. Mycophenolic acid has been evaluated as induction and remission maintenance agent in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Since the course of disease of AAV usually requires long term immunosuppression, mycophenolate has been explored as a less toxic agent compared to cyclophosphamide and azathioprine. Mycophenolate is a potent immunosuppressive agent in the therapy of AAV, non-inferior to other available drugs with comparable side effect profile. Therefore, it could be a valuable alternative in cases of toxicity with life threatening side effects or intolerance to cyclophosphamide or azathioprine, in cases with high cumulative dose of cyclophosphamide, but also in cases with insufficient response. Several studies have shown a higher relapse rate following discontinuation of mycophenolate or in mycophenolate treated subjects that raises concerns about its usefulness in the treatment of AAV. This review describes the efficacy of mycophenolate in AAV as remission induction agent, as remission maintenance agent, and as therapeutic option in relapsing AAV disease, the relapse rate following discontinuation of mycophenolate, and the adverse events related to mycophenolate treatment.
基金This work was supported by grants from the major clinical research projects of the First Affiliated Hospital of Xi＇an Jiaotong University （No. XJTU 1AF-CRF-2015-005） and the National Natural Science Foundation of China （No. 81670681）.
文摘Background： lmmunosuppressive agents are still inefficient in preventing biopsy-proven acute rejection （BPAR） alter expanded criteria donor （ECD） kidney transplantation. The aim of this study was to investigate the relationships between early imrnunosuppressive exposure and the development of BPAR. Methods： We performed a retrospective study of 58 recipients of ECD kidney transplantation treated with enteric-coated-mycophenolate sodium, tacrolirnus （Tac）, and prednisone. The levels of mycophenolic acid-area under the curve （MPA-AUC）0-12h and Tac C0 were measured at the 1st week and the 1st month posttransplant, respectively. The correlation was assessed by multivariate logistic regression. Results： The occurrence rates of BPAR and antibody-mediated rejection were 24.1% and 10.3%, respectively. A low level of MPA-AUC0-12h at the 1st week posttransplant was found in BPAR recipients （38.42 ± 8.37 vs. 50.64 ± 13.22, P 〈 0.01）. In addition, the incidence of BPAR was significantly high （P 〈 0.05） when the MPA-AUC0-12h level was 〈30 mg·h-1·L-1 at the 1st week （ 15.0% vs. 44.4%） or the Tac C0 was 〈4 ng/ml at the 1 st month posttransplant （33.3% vs. 21.6%）. Multivariable logistic regression analysis showed that the MPA-AUC 0-12 h at the 1st week （OR： 0.842, 95% CI： 0.784-0.903） and the Tac C0 at the 1st month （OR： 0.904, 95% C7： 0.822-0.986） had significant inverse correlation with BPA R （ P 〈 0.05 ）. Conclusions： Low-level exposure of MPA and Tac C0 in the early weeks posttransplant reflects an increased acute rejection risk, which suggested that MPA-AUC0-12h 〈30 mg·h-1·L -1 and Tac C0 〈4 ng/ml should be avoided in the first few weeks alter transplantation.
文摘目的:比较强化剂量与标准剂量霉酚酸类药物用于成年肾移植受者的有效性与安全性,为临床合理用药提供循证参考。方法:计算机检索Embase、PubMed、Cochrane图书馆、Clinical trials.gov、中国知识资源总库、万方数据、中国生物医学文献数据库,检索时限均为各数据库建库起至2020年3月,收集霉酚酸类药物[吗替麦考酚酯(MMF)、麦考酚钠肠溶片(EC-MPS)]强化剂量对比标准剂量用于成年肾移植受者的随机对照试验(RCT)和队列研究;筛选文献、提取资料后,采用Cochrane干预措施系统评价手册(第5版)推荐的偏倚风险评估工具对RCT进行质量评价,采用NOS量表对队列研究进行质量评价;采用Rev Man 5.3软件进行Meta分析,并进行敏感性分析。结果:共纳入8项研究,其中6项为RCT、2项为队列研究,共1637例患者。Meta分析结果显示,强化剂量组患者经活检证实的急性排斥反应(BPAR)发生率[RR=0.65,95%CI(0.48,0.89),P=0.007]、巨细胞病毒(CMV)感染发生率[RR=0.39,95%CI(0.17,0.91),P=0.03]均显著低于对照组。按药物进行的亚组分析结果显示,MMF强化剂量组[RR=0.72,95%CI(0.53,0.99),P=0.04]、EC-MPS强化剂量组[RR=0.19,95%CI(0.04,0.81),P=0.03]患者的BPAR发生率均显著低于标准剂量组;MMF强化剂量组[RR=0.16,95%CI(0.02,1.33),P=0.09]、EC-MPS强化剂量组[RR=0.51,95%CI(0.20,1.30),P=0.16]患者的CMV感染发生率与标准剂量组比较,差异均无统计学意义(P>0.05)。两组患者排斥反应、治疗失败、移植物丢失、终止治疗、病死、总体不良事件、感染(总体)、BK病毒感染、尿路感染、血液系统不良事件(总体)、白细胞减少、贫血、血小板减少、胃肠道不良事件(总体)、恶心、呕吐、腹泻等发生率比较,差异均无统计学意义(P>0.05)。敏感性分析结果显示,排斥反应、CMV感染、白细胞减少发生率的结果稳定性一般。结论:早期强化剂量霉酚酸类药物用于成年肾移植受者的有效性、安全性与标准剂量总体相当,虽然强化剂量可降低BPAR及CMV感染的发生风险,但结合敏感性分析结果,建议应谨慎解读排斥反应、CMV感染、白细胞减少发生率等结果。
文摘目的:观察肝移植术后早期麦考酚钠肠溶片(enteric-coated mycophenolate sodium,ECMPS)药代动力学特点.方法:25例肝移植受者术后联合应用他克莫司Tacrolimus(FK506)和EC-MPS治疗.ECMPS口服剂量为720 mg,2次/d.术后7、21 d分别在服药前及服药后1、1.5、2、2.5、3、4、6、8和12 h取外周血,采用高效液相色谱法(high performance liquid chromalography,H P L C)测定血浆麦考酚酸(m yc o p h e n o l i c acid,MPA)浓度.WinNonlin软件计算MPA药时曲线下面积(area of concentration-time under the curve,AUC).同时测定FK506谷浓度(FK506-C0 h)及肝、肾功能和血细胞记数.结果:合并43套数据,MPA-AUC0-12 h平均为40.36(μg·h)/mL±17.20(μg·h)/mL,Cmax为16.66μg/mL±9.73μg/mL,Tmax为3.14 h±1.78 h.MPA-C0 h-C12 h与MPA-AUC0-12 h的相关性不显著(r2<0.75).MPA-AUC0-12 h与FK506-C0 h、血清白蛋白水平及肌酐清除率显著相关性(P>0.05).结论:肝移植后早期患者服用EC-MPS MPAAUC0-12 h个体间差异很大;单个时间点MPA浓度不能有效反映MPA-AUC0-12 h;FK506-C0 h、血清白蛋白水平及肌酐清除率不影响MPAAUC0-12 h.
