CAJ | 학술논문

目的测定肾移植术后稳定期受者吗替麦考酚酯(MMF)暴露量,明确其影响因素,探究与药物不良反应之间的关系.方法以首次接受肾移植的成年受者为研究对象,术后随访时间为3～5年.通过有限取样法测定MMF暴露量,应用多元回归模型研究0～12 h麦考酚酸(MPA)血浆浓度-时间曲线下面积值(AUC0-12)的影响因素.按照MPA AUC州2结果分为3组(＜30 mg·h·L-1组、30～60 mg·h·L-1组、＞60 mg·h·L-1组),统计不良反应发生情况.结果共有39例受者入组,其中女性20例,男性19例.10例受者(25.6％)曾因术后出现不良反应而减少MMF剂量至1 g/d,其余受者剂量为1.5 g/d.服药前(C0)、服药后0.5 h(C0.5)和服药后2 h(C2)血药浓度分别为(3.73±1.93) mg/L、(17.20±12.46) mg/L、(9.64±4.33) mg/L,MPA AUC0-12为(57.30±22.60)mg·h·L-1,39例中MPA AUC0-12＜30 mg·h·L-1组4例、30～60 mg·h·L-1组17例、＞60 mg·h·L-1组18例,而剂量校正AUC0-12 (AUC0-12/剂量)则为(43.00±19.64)mg·h·L-1·g-1.多元回归方程可以解释约60％的MPA AUC12差异,最终模型所纳入的变量包括血糖、白细胞计数、年龄、天冬氨酸转氨酶、尿蛋白.最近6个月内共有38例次出现MMF相关的不良反应,通过二分类logistic回归分析分别研究C0、C0.5、C2、剂量、AUC0-12、AUC0-12/剂量等变量对于MMF相关不良反应的影响,结果均无统计学意义(P＞0.05).在比较30～60 mg·h·L-1组和＞60 mg·h·L-1组不良反发生率后发现,胃肠道不良反应、血液系统不良反应、感染和恶性肿瘤发生率的差异均无统计学意义(P＞0.05).结论相对于30～60mg·h·L-1的推荐范围,稳定期受者MPA AUC0-12较高,其主要影响因素包括血糖增高及出现蛋白尿.不良反应发生率较低,且与MMF暴露量之间无明显相关性.
목적 측정신이식술후은정기수자마체맥고분지(MMF)폭로량,명학기영향인소,탐구여약물불량반응지간적관계.방법 이수차접수신이식적성년수자위연구대상,술후수방시간위3～5년.통과유한취양법측정MMF폭로량,응용다원회귀모형연구0～12 h맥고분산(MPA)혈장농도-시간곡선하면적치(AUC0-12)적영향인소.안조MPA AUC주2결과분위3조(＜30 mg·h·L-1조、30～60 mg·h·L-1조、＞60 mg·h·L-1조),통계불량반응발생정황.결과 공유39례수자입조,기중녀성20례,남성19례.10례수자(25.6％)증인술후출현불량반응이감소MMF제량지1 g/d,기여수자제량위1.5 g/d.복약전(C0)、복약후0.5 h(C0.5)화복약후2 h(C2)혈약농도분별위(3.73±1.93) mg/L、(17.20±12.46) mg/L、(9.64±4.33) mg/L,MPA AUC0-12위(57.30±22.60)mg·h·L-1,39례중MPA AUC0-12＜30 mg·h·L-1조4례、30～60 mg·h·L-1조17례、＞60 mg·h·L-1조18례,이제량교정AUC0-12 (AUC0-12/제량)칙위(43.00±19.64)mg·h·L-1·g-1.다원회귀방정가이해석약60％적MPA AUC12차이,최종모형소납입적변량포괄혈당、백세포계수、년령、천동안산전안매、뇨단백.최근6개월내공유38례차출현MMF상관적불량반응,통과이분류logistic회귀분석분별연구C0、C0.5、C2、제량、AUC0-12、AUC0-12/제량등변량대우MMF상관불량반응적영향,결과균무통계학의의(P＞0.05).재비교30～60 mg·h·L-1조화＞60 mg·h·L-1조불량반발생솔후발현,위장도불량반응、혈액계통불량반응、감염화악성종류발생솔적차이균무통계학의의(P＞0.05).결론 상대우30～60mg·h·L-1적추천범위,은정기수자MPA AUC0-12교고,기주요영향인소포괄혈당증고급출현단백뇨.불량반응발생솔교저,차여MMF폭로량지간무명현상관성.
Objective To measure mycophenolate mofetil (MMF) exposure of renal transplantation recipients in stable stage,and to investigate the effects of covariates on the pharmacokinetic parameters and their association with drug-related adverse events (AEs).Method De novo adult renal allograft recipients were selected in this study,of whom the postoperative followup time was between 3 to 5 years.A limited sampling method was performed to determine MMF exposure.Clinical determinants of the area under the curve of mycophenolic acid (MPA AUC0-12) were investigated in a multivariate regression model.All recipients enrolled were divided into 3 groups (＜ 30 mg· h· L-1,30-60 mg· h· L-1,＞ 60 mg · h· L-1) according to the pharmacokinetic study.Drugrelated AEs were recorded in the database.Result Thirty recipients (20 females,and 19 males) were included in this study.Ten of 39 recipients (25.6％) underwent dosage reduction to 1 g/day for the presence of AEs and daily dose of the rest remained 1.5 g/day.C0,C0.5 and C2 were 3.73 ± 1.93,17.20± 12.46,and 9.64±4.33 mg/L,respectively.MPA AUC0-12 was (57.30±22.60) rng·h·L-1,and low MPA AUC0-12 group (＜30 mg·h·L-1) was consisted of 4,median MPA AUC0-12 group (30-60 mg·h· L-1) 17,and high MPA AUC0-12 group (＞60 mg·h·L-1) 18.AUC0-12/dose was (43.00 ± 19.64) mg·h·L-1.Almost 60％ of MPA AUC0-12 could be explained by the final model,in which blood glucose,white blood cells (WBC),age,aspartate aminotransferase (AST) and the presence of proteinuria were independent determinants of MPA exposure.There were 38 MMF-related AEs observed in the past 6 months.Logistic regression was used to associate C0,C0.5,C2,dose,AUC0-12,AUC0-12/dose with clinical outcomes and none was significant (P＞0.05).There was no significant difference between 30-60 mg· h· L-1 group and ＞ 60 mg· h · L-1 group in the incidence of gastrointestinal,haematological,infectious and malignant AEs,either (P ＞ 0.05).Conclusion According to the recommended ranges between 30 and 60 mg h L-1,MMF exposure of stable stage recipients was higher.To a great extent,MPA AUC0-12 is associated with increased blood glucose and the presence of proteinuria.The incidence of AEs was relatively low compared with peri-operative data and no significant relationship with pharmacokinetic parameters was found in our study.