环孢素新剂型Neoral在肾移植中的应用

对10例肾移植患者作山地明转换Neoral试验进行药效动力学对比研究，30例新移植患者应用Neoral进行临床观察。结果表明，Neoral最高血浓度（Cmax）较山地明高282±84ng／ml，达峰时间（Tmax）短0．79±0．29h，CSA暴露（AUC）大1533±169ng／（h·ml）（P＜0．05）。提示Neoral有较好地抗排斥反应作用，但由于吸收迅速，血药浓度易超过治疗窗水平而引起毒副反应。本组肝中毒达20％。认为Neoral与山地明转换比例应为1：0．8～1：0．9，以避免毒副作用发生；Neoral服药量可较山地明常规剂量减少25％。     

口服他克莫司血药浓度-时间曲线下面积

目的　探讨口服他克莫司 (Tacrolimus ,FK5 0 6 )的药代动力学规律 ,寻求临床上准确反映早期药物浓度时间曲线下面积 (AUC)的监测方法。　方法　 16例肾移植受者首剂口服 0 .0 75mg/kgFK5 0 6后 ,采用ELISA法测定服药后 0 .5、1.0、1.5、2 .0、3.0、5 .0、8.0、12 .0h时间点血药浓度 ,采用 3p87药代动力学计算程序将测得的FK5 0 6浓度自动拟合计算出AUC ,并分别将各时间点血药浓度与AUC进行相关性检验 ,计算相关系数。　结果　AUC变化范围为 4 4 .4 0～ 15 8.0 1μg·h-1·L-1,平均 ( 92 .2 3± 34.97) μg·h-1·L-1,个体间AUC可相差 4倍 ;血药谷浓度Cmin与AUC之间的相关性有显著差异 (P <0 .0 0 1,rmin=0 .6 5 0 )。　结论　首剂口服同一剂量FK5 0 6后 ,个体间药物浓度时间曲线下面积差异很大。Cmin能准确反映首剂口服FK5 0 6后的AUC ,临床上可通过监测Cmin达到FK5 0 6早期剂量的个体化     

中国成人肝移植受体服用微乳化环孢素A两小时后浓度监测

目的评估微乳化环孢素A(CsAME)服用2h后药物浓度(C2)监测的安全性和可靠性,初步确定适合中国成人肝移植受体的C2目标浓度。方法将53例肝移植术后1～2个月的中国成人肝移植受体随机分为C0组(n=17)、高浓度C2组(n=18)、低浓度C2组(n=18),每组均设定了相应的目标浓度,随访期间定期监测CsA浓度、心、肝、肾功能、机体免疫状态及排斥反应的发生情况。结果低浓度C2组口服CsA的剂量最低,仅为2.51±0.37mg·kg-1·d-1,与C0组和高浓度C2组相比差异具有显著性(P<0.01)。低浓度C2组心、肝、肾功能受损程度最小,高浓度C2组受损伤程度最重。低浓度C2组的CD+4/CD+8T细胞比值为1.04±0.68,与C0组无显著性差异(P>0.05)。各组的排斥反应发生率无显著性差异。低浓度C2组的临床获益率最高(72.22%),高浓度C2组最低(11.11%)。结论通过设定合理的目标浓度,C2监测可以提供更合理的CsA口服剂量,在明显降低毒副作用的同时不增加排斥反应的发生率。适合中国成人肝移植受体的术后CsAMEC2目标浓度初步确定为:术后1～6个月600～800ng/ml,术后7～12个月400～600ng/ml。     

成人肝移植供受体CYP3A5基因分型对术后他克莫司临床个体化用药的应用价值探讨

目的探讨成人肝移植供受体CYP3A5基因分型与术后他克莫司药物代谢的关系。方法回顾性收集天津市第一中心医院2018年7月至2019年6月期间施行的肝移植的供受体各98例为研究对象,术前收集肝移植受体和供体血,通过PCR法检测供受体的CYP3A5基因型,并收集术后1、2、3及4周的他克莫司浓度/剂量比。结果在98例肝移植供受体的CYP3A5基因分型中,均以GG型最多、AA型最少,且等位基因分布符合遗传规律,差异无统计学意义(P0.05)。术后1、2、3及4周时,不管是在供体还是在受体中,3种基因型组的他克莫司浓度/剂量比两两比较差异均有统计学意义(P0.05),GG型最高,AA型最低。联合供体和受体的基因型进行联合分组分析,结果表明,术后1、2、3及4周时,A*/A*、A*/GG、GG/A*和GG/GG组的他克莫司浓度/剂量比两两比较差异均有统计学意义(P0.05),GG/GG型最高,A*/A*型最低。结论供受体的CYP3A5基因分型可以影响受体肝移植术后他克莫司的血药浓度,CYP3A5 GG基因型比其他基因型更容易达到目标血药浓度,检测肝移植患者供受体CYP3A5基因型可以为受体肝移植术后他克莫司的个体化治疗提供参考。     

肝移植术后FK506个体化应用的研究进展

FKS06是肝移植术后常用的免疫抑制剂,存在治疗窗狭窄、个体间和个体内变异性大等特点.对移植患者术后血药浓度的监测是目前临床免疫抑制方案调整的主要依据,但仍缺乏较稳定的预见性和指导性.以遗传多态性为基础的药物基因组学的发展为个体化用药提供了更为合理的发展方向.目前国内外的器官移植领域个体化免疫抑制治疗相关研究多围绕细胞色素代谢酶(P450)、P-糖蛋白(PgP)及核内受体编码基因的多态性展开.     

犬辅助性原位肝左叶移植模型的建立

目的建立稳定可靠的辅助性肝移植动物模型。方法杂交犬14条8～25kg随机分两组。供体组肝脏均采用尸体肝左叶；受体组行标准左叶切除，供肝左叶原位移植于受体体内。结果供肝热缺血时间为零，冷缺血时间平均36．3min；灌注液的量平均2．96L，切取修剪肝左叶时间为23～40min。受体手术平均时间5．3h，平均出血量140ml，肝脏血管重建后红润柔软，5～11min内即见胆汁从胆管中溢出。受体组术后全部存活，围手术期未用任何血管活性药物、抗生素及免疫抑制剂。术后存活超过6h者5例．最长存活者达5．7d。结论犬是建立辅助性肝移植模型的理想动物。     

小型猪小体积肝移植模型的建立

目的研究构建成熟稳定小型猪小体积肝移植模型的方法。方法选用体重一致的广西巴马小型猪20只,按照随机原则分为供体组和受体组各10只。在获取供肝的过程中即进行减体积操作,切除左半肝并保留肝中静脉主干。受体采用经典原位非静脉-静脉转流法行小体积肝移植。记录受体肝移植的手术时间,供肝热缺血时间、冷缺血时间,受体无肝期时间。观察移植术后2周存活情况及手术相关并发症。结果手术时间5～7h,平均6h;供肝热缺血时间2～3min;冷缺血时间(116±16)min;无肝期时间(35±4)min。术中小型猪均无死亡。10只受体猪中,2只死于手术相关并发症,其中1只于术后10h死于肝断面出血,另1只于术后2d死于切口疝。其余8只受体猪皆存活超过2周,2周存活率达80%,均未发生手术相关并发症。结论在供体手术中切除左半肝并保留肝中静脉主干,受体采用经典原位非静脉-静脉转流法行小型猪小体积肝移植模型构建是可行且稳定的。     

成人-儿童间双供体活体肝脏移植一例报告

在活体肝移植中,供肝移植物达到受体标准肝体积的50%是满足受体正常肝功能的必要条件[1],主要的解决方法是切取供体占全肝60%～70%的右半肝、采用辅助式原位肝移植或给一个受体植入2个移植物.既往文献报道中,双供体活体肝移植都用于成人间[2-5],而成人-儿童间的双供体活体肝移植尚未见报道.     

新山地明在我国肾移植中用法的初步报告

目的：将新山地明（Neoral)的用法从2次／d改为3次／d，降低其毒副作用。方法：初次肾移植者60例，随机分为2组，I组：28例，2次／d;Ⅱ级：32组，3次／d,Neoral口服剂量相同。术后随访3个月。结果：Neoral 血药浓度Ⅱ组与I组相比，谷值显著上升，峰值显著下降；两组急性排斥反应率相似，但Ⅱ组毒副作用（4／32）显著低于I组（11／28），P＜0．01，结论：将Neoral的用法从2次／d改为3次／d，可以显著降低其毒副作用，尤其是肝毒性，并且不增加排斥反应发生率。     

血清肝炎病毒标志物阳性或肝炎患者肾移植后测定环孢素C2的意义

目的　探讨测定血清肝炎病毒标志物阳性患者或肝炎患者肾移植后服用环孢素A(CsA) 2h的血药浓度 (C2 )的临床意义。方法　共观察 1 62例肾移植患者 ,其中术前丙型肝炎病毒抗体或 /和乙型肝炎核心抗原阳性 ,或者有明确肝炎病史者 51例为阳性组 ,另 1 1 1例非肝炎患者为正常组 ,术后 1周测定服用CsA前 (C0 )及服药后 2h(C2 )的血药浓度 ;术后观察肝功能半年。结果　阳性组患者术后 1周的C2 明显高于正常组 (P <0 .0 1 ) ,而两个组C0 的差异无显著性 ;术后半年内阳性组的患者发生药物肝毒性的机率明显高于正常组 ,特别是术后 1周C2 超过 1 .41 4 μmol/L(1 70 0 μg/L)者 ,术后发生药物肝毒性的机率更高。结论　C2 能更充分反映个体间的差异 ,以指导个体化用药     

Pharmacokinetics of neoral in stable renal transplant recipients with long-term diabetes mellitus

Therapeutic drug monitoring (TDM) of Neoral has been studied widely and C2 monitoring has been shown to be superior to C0 monitoring in predicting outcomes. However, data are scarce in diabetic renal transplant recipients who may have gastroparesis. We studied 0 to 8 hour pharmacokinetic profiles (AUC(0-8h)) of Neoral on 3 consecutive days in 18 diabetic adults who had stable renal function for at least 6 months after transplantation and no overt symptoms of diabetic gastroparesis. All patients had diabetes mellitus (DM) for at least 5 years. Intrapatient variability of C2 levels was 28% (range, 6%-68%); it was < or =20% in 9 patients (50%) and >60% in 2 patients. Correlation coefficients between AUC(0-8h) and AUC(0-4h), between C2 and AUC(0-8h), and between C0 and AUC(0-8h) were 0.95, 0.86, and 0.77, respectively. Exposure phase (85% of AUC(0-8h)) was longer than 4 hours in all completed (48/54; 89%) profiles; it was longer than 6 hours in 20 profiles. C4 levels had good correlation with AUC(0-8h) (0.86) and low intrapatient variability (16% +/- 11%; range, 2%-39%). Thirteen of 18 patients (72%) had intrapatient variability of C4 < or = 20%. We conclude that the exposure phase of Neoral is prolonged more than 4 hours in adult renal transplant recipients with long-term diabetes, even in the absence of symptoms of gastroparesis. Because of very high intrapatient variability in this group of patients, C2 levels may not be reliable for TDM of Neoral despite high correlation with AUC(0-8h). C4 level may be a valid alternative for these patients.     

Reduced variability of Neoral pharmacokinetic studies in pediatric renal transplantation

In adult renal transplant recipients the Neoral area under the curve (AUC) displays less inter- and intra- individual variability than Sandimmune, and those renal transplant recipients with reduced intra-individual variability of the AUC have a lower risk for chronic rejection. As variability of Neoral pharmacokinetic (Pk) parameters has not been investigated in pediatric renal transplant recipients, we retrospectively analyzed 453 Pk profiles in 14 pediatric patients who were switched from Sandimmune to Neoral and compared the inter- and intra-individual variability of the Pk profiles on both formulations. After the switch, we observed less inter- and intra-individual variability of AUC, the 2-h concentration, and the oral clearance. As clearance with both formulations is supposedly equal, the significantly lower intra-individual variability of oral clearance is most likely an effect of less variable absorption. While the lower inter-individual variability of the Pk parameters suggests increased success in keeping cyclosporine concentrations on target, the lower intra-individual variability leads to the hypothesis that with Neoral, a lower incidence of chronic rejection might be achieved. Received: 8 February 2000 / Revised: 17 May 2000 / Accepted: 22 May 2000     

Efficacy of C0 and C2 monitoring in adult liver transplant recipients treated with neoral, mycophenolate mofetil, and steroids

BACKGROUND: Adjustment of induction therapy with Neoral after liver transplantation according to C2 levels yields a reduced incidence of rejection compared with C0 monitoring. A combination with mycophenolate mofetil may further reduce episodes of acute rejection. The purpose of this analysis was to evaluate the predictive value of C0 and C2 monitoring and the influence of primary dysfunction in liver transplant recipients receiving induction therapy with Neoral, mycophenolate mofetil, and steroids. PATIENTS AND METHODS: One hundred consecutive adult liver transplant recipients were analyzed. Neoral doses were solely adjusted according to C0 target levels in the first week by daily analysis of C0 levels. C2 levels were also measured, but results did not influence the decision process of daily Neoral adjustments. RESULTS: The 3-month survival rate for all patients was 83%. For a further analysis, 35 patients were excluded, the remaining 65 patients experienced 15 rejections (23.1%). Patients who did reach C0 target levels by days 3, 5, or 7 had rejection rates no different from those who did not reach C0 target levels. The patients who did reach C2 target levels by day 7 showed a significantly lower rejection rate compared with those who did not reach these levels. Comparison of rejection rates among patients with primary function grades I and II versus grades III and IV revealed a significant difference. There was no correlation between Model for End-Stage Liver Disease (MELD) score and acute rejection episodes. CONCLUSION: Achievement of C2 target levels by day 7, especially in the combination of Neoral with mycophenolate mofetil, led to a remarkably low acute rejection rate following liver transplantation.     

NOF-11: a one-year pediatric randomized double-blind comparison of neoral versus sandimmune in orthotopic liver transplantation

BACKGROUND: Although cyclosporine (CsA) has been a mainstay in liver transplantation immunosuppression the original formulation [Sandimmune (SIM)] has variable absorption, particularly in children. Neoral is a new formulation of CsA that may have improved biovailability that would be advantageous in children. This study was undertaken to assess the pharmacokinetics (PK) and effects on outcome of Neoral versus Sandimmune (SIM) in primary pediatric liver transplant recipients. METHODS: Thirty-two patients were randomized to receive Neoral (17 patients) or SIM (15 patients) in the early posttransplant period (days 1-7) in a double-blind fashion. Intravenous CsA was instituted immediately posttransplant followed by Neoral or SIM as soon as the patient was tolerating oral fluids (days 1-7). PK were compared after the first dose (1-7 days), 3 weeks, and 6 and 12 months posttransplant. In addition, side effects, effect of age and food on absorption, and rejection episodes were assessed by intent to treat analysis. Notable characteristics of this study include the use of a central laboratory for all sample analyses and the assessment of renal function using radioisotopic evaluation of glomerular filtration rates. RESULTS: At baseline the two groups were comparable. Neoral resulted in higher peak levels of CsA and total drug exposure with comparable time to peak drug levels at days 1-7 and week 3. This trend was maintained at 6 and 12 months. Time on i.v. CsA was reduced in the Neoral group (8.4 vs. 11.1 days) and the weight adjusted daily dose of SIM required to achieve target trough levels was about 2-fold more than Neoral from day 22 onward. In addition, biopsy proven and treated and steroid-resistant rejection episodes were fewer in the Neoral group (6 vs. 12; P=0.01 and 1 vs. 8: P=0.004, respectively). Side effects were comparable in both treatment groups. CONCLUSIONS: Neoral was well tolerated and had greater biovailability than SIM without any increase in the incidence of side effects. In addition fewer episodes of rejection were observed with Neoral versus SIM. We conclude that Neoral is the CsA formulation of choice for use in pediatric liver transplant recipients.     

Suitable whole blood levels 2 hours after neoral in liver transplant patients: experiences at a single center

Whole blood levels 2 hours after Neoral (C2) administration were observed to correlate better with area under the curve (AUC(0-4)) than trough levels (C0), suggesting that C2 may be the best single time point predictor of Neoral absorption. Owing to concerns about drug toxicity due to excessive immunosuppression, C2 adjustments to target blood levels may represent an advance. The present study measured C2 and levels to determine which correlated more closely with AUC(0-4). METHODS: Between August 2003 and July 2004, 40 adult liver transplantations were performed in our center. All patients received Neoral twice daily. They were maintained at a C0 level of about 200 ng/mL. C0 levels were measured daily. C2 levels were estimated on postoperative days 3, 5, 7, 14, and 28. AUC(0-4) performed on postoperative days 3, 7, and 28 was calculated using the trapezoidal rule. RESULTS: The mean AUC(0-4), C0, C1, C2, C3, and C4 were 1100.3 +/- 484.8 ng/mL, 197.1 +/- 84.7 ng/mL, 240.7 +/- 166.2 ng/mL, 307.8 +/- 162.6 ng/mL, 302.8 +/- 138.9 ng/mL, and 300.3 +/- 142.8 ng/mL, respectively. C2 correlated with AUC(0-4) (R2 = 0.868: P < .05) better than C0 (R2 = 0.245: P < .05), C1 (R2 = 0.604: P < .05), or C4 (R2 = 0.583: P < .05). CONCLUSIONS: Neoral dose monitoring according to a mean C2 range of 307.8 +/- 162.6 ng/mL correlated better with AUC(0-4). Further studies are required to determine suitable C2 levels in liver transplant patients.     

Switchover to generic cyclosporine in stable renal transplant recipients: a single unit experience

BACKGROUND: The introduction of the immunosuppressant cyclosporine has significantly improved renal transplant survival. It is an expensive drug and generic alternatives may offer cost advantages. However, generic alternatives must be shown to provide equivalent therapeutic efficacy and safety. This study reports our experience of a switch from the microemulsion formulation of cyclosporine, Neoral (Novartis), to the generic equivalent, Cysporin (Mayne Pharma). METHOD: A two-period, single-sequence, cross-over study was done to compare cyclosporine blood levels and the area under the curve (AUC) of Neoral with Cysporin 2 weeks after a 1:1 dose switch. cyclosporine blood levels were measured at time points 0, 2, 4 and 8 h (C0, C2, C4, C8) after the switch. The cyclosporine AUC at 0-4 h and 0-12 h were calculated using the trapezoidal method. The two formulations were considered to result in equivalent blood levels if the 95% confidence interval (CI) of the ratio of the two levels was within 0.8-1.25. RESULTS and CONCLUSION: A total of 38 stable renal transplant patients aged 49.79 +/- 11.38 years (mean +/- SD), who were 7.84 +/- 3.97 years postrenal transplantation, were studied. The Neoral dose at the time of the switch was 2.38 +/- 1.21 mg per kg bodyweight. At all measured time points the 95% CI for the cyclosporine drug level ratio was between 0.9 and 1.15. There were no significant adverse events during the period of study. We conclude that the generic formulation of cylosporin, Cysporin, after a 1:1 switch from Neoral results in equivalent blood levels in stable renal transplant recipients. After switchover cyclosporine levels at C0 or C2 can continue to be monitored as per the institution's current monitoring practice.     

Pharmacokinetics of oral cyclosporine (Neoral) in heart transplant recipients during the immediate period after surgery

Neoral cyclosporine has better absorption characteristics than the original Sandimmun formulation. This has allowed Neoral to be administered orally in circumstances where Sandimmun had been ineffective, including the postoperative phase of liver transplantation. Sampling strategies, such as the measurement of drug concentration 2 h after oral administration, have been used in a variety of settings to estimate systemic exposure to Neoral (measured as the area under the blood concentration curve (AUC) of the drug) in blood. We conducted a pilot study to determine whether Neoral could be administered orally immediately after heart transplantation and to determine which pharmacokinetic parameters reflect systemic drug exposure in this setting. Eight male patients (mean age 50 years) undergoing a first heart transplant were studied. Neoral was administered orally before surgery and at 12-h intervals via a nasogastric tube after surgery. Twelve-hour pharmacokinetic profiles were obtained on postoperative days 1, 3 and 5. Cyclosporine concentrations were measured with the Dade Behring Emit assay, which is specific for the parent drug. Drug concentrations were dose-normalised and drug exposure was measured by the AUC. Drug exposure following administration (AUC(0-12)) was low on day 1 but increased by 99% between postoperative day 1 and day 5 ( P<0.05), indicating more complete absorption of cyclosporine; exposure in the first 4 h post-dose (AUC(0-4)) increased by 126% ( P<0.01), reflecting more rapid cyclosporine absorption, and the maximum blood concentration observed increased by 137% ( P<0.05) during the same period. The correlation between the cyclosporine trough concentration and AUC(0-12) was low on all days. Due to the changing pattern of cyclosporine absorption, concentration measurements at a single time point could not accurately predict 12-h exposure to the drug on all study days. However, the drug concentration at 2 h post-dose had a high correlation with drug exposure during the first 4 h (correlation of C(2) to AUC(0-4): r(2)>0.93 on all days). Absorption of Neoral was low immediately after heart transplantation but improved substantially during the first 5 days after surgery. No single timed measurement of drug concentration reflected cyclosporine exposure; however, the 2-h concentration did provide an accurate measure of the early phase of drug absorption (AUC(0-4)). Oral administration of Neoral may result in inadequate immunosuppression immediately after heart transplantation unless it is supplemented either by intravenous cyclosporine or by the use of an induction agent.     

Comparison of pharmacokinetics of Neoral and Sandimmune in stable pediatric liver transplant recipients.

Cyclosporine (Sandimmune; Novartis Pharmaceuticals UK Ltd) is an effective immunosuppressive drug, but its lipid formulation and variable absorption may expose children to the risk of rejection during episodes of gastroenteritis after liver transplantation. Neoral (Novartis) is a microemulsified form of cyclosporine that may be better absorbed. In this study, the pharmacokinetic profiles of Neoral and Sandimmune were compared in stable children after liver transplantation to evaluate whether Neoral is more predictably absorbed. Eight children, 6 boys and 2 girls, with a mean age of 4.5 years (range, 1.2-12) were studied between 4 and 12 months after liver transplantation. Pharmacokinetic profiles were performed on each child by using the same dose (mg/kg) of Neoral or Sandimmune. Tmax, Cmax, Ctrough, and the area under the curve (AUC) were calculated and side effects were documented in children taking either drug for more than 3 months. Mean peak cyclosporine levels were higher and were achieved significantly sooner with Neoral (Cmax 790.5 +/- 216.5 ng/mL, P =.06; Tmax 1.8 +/- 1.0 hr, P =.01) than with Sandimmune (Cmax 589.4 +/- 313 ng/mL, Tmax 2.5 +/- 1.7 hr), implying more rapid and better absorption. There was no significant difference in overall drug exposure (AUC) and 12-hour trough levels between the two formulations (P >.05). Children with Roux-en-Y loop biliary anastomosis taking Neoral, however, showed greater increases in AUC (mean increase = 37%) than those with duct-to-duct anastomosis (mean increase = 16%). There was no correlation between 12-hour trough level and AUC for either Neoral (r2 = 0.48) or Sandimmune (r2 = -0.08); however, for both drugs, AUC correlated very well with the 2-hour post-dose level (r2 = 0.68 and 0.7, respectively). Hirsutism was reported in 4 of 6 children on Neoral and may be associated with higher peak levels. Neoral is more consistently absorbed than Sandimmune in children after liver transplantation and may be more effective prophylaxis against rejection. Because of the increased peak levels and drug exposure, which may influence side effects, particularly in children with Sandimmune malabsorption, we recommend a 1:0.75 dose conversion ratio in patients being converted from Sandimmune to Neoral.     

Neoral in de novo liver transplantation: Adequate immunosuppression without intravenous cyclosporine

Absorption of cyclosporine from the traditional oral formulation Sandimmune (Novartis Pharma, Basel, Switzerland) is particularly unpredictable in the early stages after liver transplantation. The absorption of cyclosporine is influenced by liver function, postoperative paralytic ileus, and graft dysfunction. Oral absorption of cyclosporine from Sandimmune is also bile dependent; cholestasis and external biliary drainage are associated with low cyclosporine absorption. Postoperative administration of intravenous Sandimmune is therefore often necessary to obtain adequate immunosuppression, despite the increased risk of renal and neurological toxicity. A microemulsion formulation of cyclosporine, Neoral (Novartis), has been developed to overcome the problems of poor and variable absorption of cyclosporine from Sandimmune. Uptake of cyclosporine from Neoral is rapid and less dependent on bile secretion so that higher peak concentrations are reached and absorption is less variable than with Sandimmune. A review of several open studies in which Neoral was administered to liver transplant patients immediately after transplantation is presented. The results suggest that the use of Neoral as a primary immunosuppressive therapy provides adequate cyclosporine trough levels, minimizing or obviating the need for intravenous cyclosporine administration. In addition, Neoral appears to reduce the risk of acute rejection episodes compared with immunosuppressive regimens involving intravenous cyclosporine. (Liver Transpl Surg 1997 Nov;3(6):571-7)     

Monitoring C2 level predicts exposure in maintenance lung transplant patients receiving the microemulsion formulation of cyclosporine (Neoral).

BACKGROUND: Dosing of the microemulsion formulation of cyclosporine (Neoral) is conventionally based on trough levels (C(0)). However, experience in renal transplantation has shown that cyclosporine exposure during the absorption phase (AUC(0-4)) is critical for optimizing immunosuppression, and that cyclosporine (CsA) concentration at 2 hours post-dose (C(2)) shows the closest correlation with AUC(0-4). This study evaluated whether C(2) values correlate more closely with AUC(0-4) than C(0) in lung transplant patients. METHODS: Pharmacokinetic data were collected prospectively from 20 clinically stable adult lung allograft recipients receiving CsA, mycophenolate mofetil and steroids. Indications for transplantation were emphysema (n = 15), idiopathic fibrosis (n = 2), primary pulmonary hypertension (n = 1), cystic fibrosis (n = 1) and lymphangioleiomyomatosis LAM (n = 1). Blood samples were collected at 0, 1, 2, 3 and 4 hours after administration of CsA, and then AUC(0-4) was calculated. The Correlation between cyclosporine concentration at each time-point and AUC(0-4) was also calculated. RESULTS: C(2) showed the closest correlation with AUC(0-4) (r(2) = 0.85). C(0) had the poorest correlation of all time-points (r(2) = 0.64). Two patients with radiologic signs of gastroparesis had no peak cyclosporine levels at all and were excluded from the correlation analysis. Mean AUC(0-4) was 3,700 ng . h/ml during Year 1 post-transplant, 2,400 ng . h/ml during Years 1 to 3, and 1,500 ng . h/ml thereafter. Mean C(2) values were 1.2 microg/ml during Year 1, 0.8 microg/ml during Years 1 to 3, and 0.5 microg/ml thereafter. CONCLUSIONS: C(2) is the single time-point that correlates most closely with AUC(0-4) in lung transplant recipients without gastroparesis. It remains to be demonstrated whether monitoring CsA based on C(2) levels results in a lower incidence of rejection without additional toxicity.