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     

服用微乳化环孢素A的长期存活肾移植患者血环孢素浓度监测的回顾性分析

目的 探讨服用微乳化环孢素A(CsA)的长期存活肾移植受者血CsA浓度监测的意义。方法 回顾性分析126例存活1年以上的肾移植患者术后血CsA浓度的资料，入选受者术后存活1～17年，随访期间患者均接受微乳化CsA、霉酚酸酯(或硫唑嘌呤)及泼尼松预防排斥反应，CsA浓度测定采用免疫荧光偏振TDx法。分析服药后2h血CsA浓度(C2)变化及其与药物剂量、移植肾功能之间的关系。结果 C2随术后时间的延长逐渐降低，但个体间的变异度随时间延长而逐渐加大；肾移植后的前5年，C2与服药剂量以及移植肾功能呈显著正相关关系，肾移植后10年以上的受者C2与肾功能关系不明显。结论 对于存活1年以上的肾移植受者，C2仍然是药物凋控的一个有效指标，但随移植时间的延长，C2的变异度逐渐加大。     

心脏移植患者服用微乳化环孢素A后的血药浓度C2值监测及意义

目的 评估心脏移植患者口服微乳化环孢素A(CsA)后2 h时的血药浓度(C2)作为临床监测指标的安全性和准确性.方法 107例心脏移植受者,除29例研究阶段移植的患者外,其余为定期随访患者.心脏移植术后口服微乳化CsA(以下"CsA"均指微乳化CsA)预防排斥反应,其中54例以服用CsA前即刻血药浓度(C0)为监测指标(C0组),另53例以C2为监测指标(C2组),所有患者入组时血肌酐(Cr)<150 tmaol/L,丙氨酸转氨酶(ALT)<80 U/L.在测定血药浓度的同时,检查心脏及肝、肾功能.结果 C0组和C2组肝损害发生率分别为25.0%(13/52)和10.0%(5/50);肾损害发生率分别为5.8%(3/52)和8.0%(4/50);急性排斥反应发生率分别为11.5%(6/52)和6.0%(3/50).C0组中,未发生排斥反应者的C2为(0.131±0.074)μmol/L,低于发生排斥反应者的(0.133±0.078)μmol/L,但二者间的差异无统计学意义(P0.05);发生不良反应(肝、肾毒性)者的C0为(0.133±0.075)μmol/L,无不良反应者的C0为(0.131±0.073)tanol/L,二者间的差异无统计学意义(P0.05).C2组中,未发生排斥反应者的C2为(0.659±0.296)μmol/L,高于发生排斥反应者的(0.516±0.217)μmol/L(P<0.05);发生不良反应者的C2为(0.719±0.288)μmol/L,无不良反应者的C2为(0.579±0.271)tanol/L,后者明显低于前者(P<0.05).结论在提示急性排斥反应和CsA所致不良反应的准确性方面,C2均明显优于C0.     

尼卡地平对肾移植受者环孢素A血浓度的影响

目的：研究尼卡地平对肾移植受者血压和环孢素A（CaA)全血谷值浓度的影响。方法：试验组62例肾移植术后肾功能恢复正常的受者服用尼卡地平，服药前后作自身对照；23例受者服用硝苯地平作为对照组，以CsA全血谷值浓度、CsA剂量、肌酐、血压作为临床评价指标。结果：试验组受者服用尼卡地平后CsA血药浓度显著升高、血压下降并维持在正常范围，与服用尼卡地平前比较，差异均有显著性意义（P＜0．01），6个月后环孢素剂量A减少达34．2％，对血肌酐无明显影响。结论：尼卡地平用于肾移植术后能有效治疗和预防高血压，并可提高CsA血药浓度，减少CsA用量和费用，并不增加CsA的毒性反应。尼卡地平与CsA合用可节省费用。     

服用微乳化环孢素A胶囊的中老年肾移植患者的血药浓度监测

目的寻求适合中老年肾移植患者的血环孢素A(CsA)浓度。方法135例肾移植患者,按年龄分为2组,青年组96例,年龄(37.0±9.0)岁;中老年组39例,年龄(56.3±5.7)岁。均采用微乳化CsA胶囊、霉酚酸酯(MMF)及皮质类固醇激素预防排斥反应,测定术后1周、2周、3周、1个月、3个月、6个月及1年时的血CsA浓度谷值(C0)和峰值(C2),观察并比较两组肾移植术后的临床疗效及安全性。结果人、肾1年存活率,青年组分别为92.7%和87.5%,中老年组分别为94.9%和92.3%(P>0.05);1年内的急性排斥反应的发生率,青年组为22.9%,中老年组为17.9%(P>0.05);CsA的肝、肾毒性发生率,青年组为26.0%,中老年组为23.1%(P>0.05);肺部感染发生率,青年组为25.0%,中老年组为28.2%(P>0.05)。术后各个时期中老年组的CsA用量及C2均低于青年组(P<0.05)。结论中老年肾移植患者服用微乳化CsA胶囊时,其用量和需维持的血药浓度均应低于常规值。     

发生环孢素A肝损害者的环孢素A药代动力学研究及意义

目的 研究发生环孢素A（CsA）肝损害的肾移植患者口服CsA胶囊的药代动力学特点及意义。方法 测定32例服用CsA胶囊后发生肝功能异常者的血CsA浓度谷值（C0）及峰值（Cmax）、达到峰值的时间（Tmax）、浓度时间曲线下面积（AUC）及CsA清除率（CI）,统计出现CsA肝损害的时间、肝功能异常的程度、CsA的用量,并针对肝功能异常程度的不同给予不同的治疗方案;以30例肝功能正常的肾移植患者作对照。结果 随着肝功能异常程度的加重,C0有明显上升趋势,Cmax有明显下降的趋势,Tmax明显延长,中、重度肝功能异常者的C0与AUC的相关性差;对轻度肝功能异常者,可根据其CsA的AUC适当减少CsA的用量,而中、重度肝功能异常患者,治疗时应增加其它肝毒性较小的免疫抑制剂的用量,并根据其CsA的AUC将CsA的用量减少1／3－1／2,甚至停用CsA,改为肝毒性较小的药物。结论 发生CsA肝损害的患者,其CsA药代动力学与肝功能正常者相比,差异有显著性;中、重度肝功能异常患者需定期监测CsA的AUC,采取个体化治疗方案。     

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。     

环孢素A药代动力学的个体差异对术后早期移植肾功能的影响

目的　探讨服用环孢素A(CsA)的肾移植受者药代动力学特性与术后早期移植肾急性排斥及CsA肾中毒的关系。方法　 4 7例肾移植受者术后服用CsA 6mg·kg-1·d-1,7d后留取服药即刻及服药后 1、2、3、4、5、6、8、10及 12h的血样 ,测定全血CsA浓度 ,计算各自的药代动力学参数。根据检测后 1个月内移植肾功能状况进行分组 ,回顾分析各组受者药代动力学指标的差异。结果　 4 7例肾移植受者中 ,观察期内共有 12例出现急性排斥反应 ,7例出现CsA肾中毒 ,其余 2 8例移植肾功能稳定。急性排斥组CsA吸收半衰期 (T1/2 (a) )、清除半衰期 (T1/2 (e) )、药物清除率 (CL/F)、达峰值时间 (Tmax)及浓度 时间曲线下面积 (AUC)与肾功能稳定组比较 ,差异有显著性 ;CsA肾中毒组的T1/2 (e) 、CL/F、Tmax及AUC与稳定组比较 ,差异均有显著性。结论　通过多点浓度进行CsA的药代动力学检测可以较准确反映肾移植受者的药物暴露剂量强度 ;CsA吸收清除较快的患者 ,容易出现急性排斥 ,而清除慢的患者存在并发CsA肾中毒的危险。     

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     

肾移植术后配伍他克莫司时血霉酚酸浓度测定的有限检样法研究

目的 研究成人肾移植术后霉酚酸的药代动力学特点,建立配伍他克莫司的血霉酚酸浓度曲线下面积的有限检样方法.方法 42例成人肾移植受者,采用吗替麦考酚酯(MMF)联合他克莫司、泼尼松的三联免疫抑制方案.血霉酚酸浓度通过高效液相色谱法测定,采血点为服药前(C0)及服药后0.5、1、1.5、2、3、4、6、9和12h,用梯形面积法计算浓度曲线下面积,采用多元线性回归分析,确定相关采血点,确定有限取样方案.结果 通过多元线性回归分析得出3点估算MPA-AUC=7.297+2.819C1.5 h+3.297C4h+4.269C9 h[相关系数(r2)=0.878],4点估算的MPA- AUC=2.519+0.549C0.5 h+1.900C1.5 h+3.931C4h+4.037C9 h(r2=0.928).采用Bland & Altman分析法评估,3点法和4点法均未超出置信限范围,二者与全点AUG0-12h有较好的一致性.3点评估AUC与全点AUG0-12h差值为(11.7±8.32)mg·h·L-1,二者差值的95％置信区间为9.18～14.37 mg·h·L-1 (P＜0.01);4点评估AUC与全点AUG0-12h差值为(1.65±7.98)mg·h·L-1,二者差值的95％置信区间为-0.84～4.13 mg·h·L-1 (P＜0.01).结论 该有限检样方案适用于监测成人肾移植受者配伍他克莫司用药时血霉酚酸浓度的曲线下面积.     

Neoral吸收期血药浓度和药物暴露量在中国成人肝移植受体中的变异性分析

目的通过分析中国成人肝移植受体中Neoral吸收期血药浓度与药物暴露量的变异性，为临床上发展新的Neoral治疗药物监测方法提供理论依据。方法通过定期测定22例中国成人肝移植受体口服Neoral前及服药后1、2、3、4h的血药浓度，采用个体及群体药代动力学的方法计算出个体内和个体间变异系数(CV）。结果Neoral血药浓度和AUC0～4的个体内和个体间变异系数均在服药头2h达到高峰，此后逐渐下降。术后10～11d个体间的浓度及AUC变异系数均最高。结论Neoral吸收期的变异性主要集中在服药后头2h。服药后1w左右是变异性最大的时期。     

Assessment of cyclosporine pharmacokinetic parameters to facilitate conversion from C0 to C2 monitoring in heart transplant recipients

BACKGROUND: Cyclosporine (CsA) 2-hour postdose (C2) monitoring is recommended to assess CsA exposure and predict clinical outcomes among heart transplant recipients. We correlated pharmacokinetic parameters and clinical outcomes in stable long-term heart transplant recipients monitored with C0 to develop an algorithm to convert patients from C0 to C2 monitoring. METHODS: Paired CsA C0-C2 measurements and serum creatinine levels were obtained from 35 heart transplant recipients more than 2 years posttransplantation (mean 8.8+/-4.7 years). RESULTS: The mean CsA dose and C0, C2, and C0/C2 ratio were 85+/-23 mg/12 hours, 123+/-41 ng/mL, 572+/-274 ng/mL and 4.8+/-2.1, respectively. C0 correlated weakly with C2 (r=.42, P=.011). The CsA dose correlated better with C2 (r=.58; P<.001) than with C0 (r=.37; P=.026). A good correlation was noted between C2 and the C2/C0 ratio (r=.73; P<.001), but none between C0 and the C2/C0 ratio. A borderline significant inverse correlation was noted between C0 and the worst endomyocardial biopsy score (r=-.34; P=.045), whereas none was noted with C2. Serum creatinine level did not correlate with either C2 or C0. Among patients with C0 within our target of 100 to 150 ug/L, six had C2 above 300 to 600 ug/L as suggested by the literature. CONCLUSIONS: In long-term heart transplant recipients, we could not identify a single pharmacokinetic parameter that could be used to develop an algorithm to convert from C0 to C2 monitoring; however, C2 may be better than C0 for identifying patients at risk of overexposure to CsA.     

Feasibility of C2 monitoring in Korean renal transplantation

BACKGROUND: In spite of efforts for simplified and optimal monitoring, variability of cyclosporine (CsA) absorption has shown limited clinical impact. We performed the present study to evaluate the feasibility of C2 monitoring and the optimal target C2 level in Korean recipients. PATIENTS AND METHODS: Sixty recipients who underwent first living donor kidney transplantations between December 2003 and May 2005 and who were treated with a regimen of CsA, mycophenolate mofetil, and steroid were enrolled in this study. CsA dose was adjusted according to conventional trough levels. Blood samples were collected just before (C0) and at 1, 2, 3, 4, 6, 8, and 12 hours (C1, C2, C3, C4, C6, C8 and C12) after dosing on days 2, 3, and 7 posttransplantation. On days 14 and 28, we determined C0, C1, C2, C3, and C4. We compared CsA levels between a no rejection versus a rejection group. RESULTS: In 8 recipients there were 1 or more acute rejection episodes (13.3%). C2 levels correlated closely with AUC0-4 on each day (r=.892-.944, P<.01), but C2 levels were not significantly different between the no rejection and the rejection group (P>.05). Mean C2 level on days 3 to 28 was significantly different between the 2 groups. (P=.045). One recipient (5.3%) with a mean C2 level greater than 1000 ng/mL underwent acute rejection. CONCLUSIONS: CsA concentration monitored as mean C2 levels early posttransplantation rather than a single point concentration on a single day was a predictor of acute rejection in kidney transplantation. Within the first month posttransplantation, the target C2 level is recommended to be over 1000 ng/mL for Korean recipients.     

Switching cyclosporine blood concentration monitoring from C0 to C2 in children late after liver transplantation

BACKGROUND: Measurement of cyclospoprine (CsA) blood levels at 2 hours after oral administration (C(2)) has been proposed as a better measurement of trough level (C(0)) due to reduced intrapatient variability, acute rejection rate and renal toxicity. The aim of the present study was to assess whether there was any advantage to conversion from C(0) to C(2) CsA blood level monitoring in children late after liver transplantation. We reviewed the data from 44 children more than 1 year after liver transplantation. We measured the daily dose of CsA and the C(0) level before switching versus the daily dose and C(2) level at 6 months after conversion, in addition to the alanine aminotransferase (ALT) activity, creatinine blood concentration, and episodes of acute rejection. RESULTS: Conversion from C(0) to C(2) monitoring was not associated with a significant change in mean daily dose of CsA, mean concentration of creatinine, ALT activity or occurrence of rejection episodes. CONCLUSION: Switching from C(0) to C(2) monitoring did not seem to proffer any benefits for children late after liver transplantation.     

Cyclosporin C(2) and C(0) concentration monitoring in stable, long-term heart transplant recipients receiving metabolic inhibitors.

BACKGROUND: Cyclosporin (CsA) dose selection is complicated by significant pharmacokinetic variability between patients. Although therapeutic drug monitoring (TDM) has proven to be a useful tool for dose individualization, the search for an effective and practical measure of clinical effect has uncovered a number of options. Monitoring the CsA concentration in a blood sample taken 2 hours after the dose (C(2)) has been utilized but has not been rigorously evaluated in all clinical situations. The aim of this study was to evaluate C(2) and trough (C(0)) CsA concentrations as surrogate markers of area under the concentration-time curve (AUC) in stable, long-term heart transplant recipients receiving CsA alone or with diltiazem and/or ketoconazole. METHODS: CsA blood concentration-time data were collected at steady state for 47 stable heart transplant recipients after the morning dose of Neoral. CsA concentration in whole blood was quantitated using the EMIT immunoassay. Patients were stratified into 4 groups, depending on the long-term concomitant administration of drugs known to inhibit CsA metabolism, as part of their routine therapy: Group A (n = 11), CsA alone; Group B (n = 10), CsA with slow-release diltiazem; Group C (n = 13), CsA with ketoconazole; and Group D (n = 12), CsA with a combination of diltiazem and ketoconazole. RESULTS: In Group A, C(2) correlated poorly with AUC(0-5) (r(2) = 0.197; p = 0.17), whereas C(0) (trough blood sample) showed a stronger correlation (r(2) = 0.710; p = 0.001). Correlations of C(0) and C(2) with AUC(0-5) were the same, but weaker in patients receiving CsA and diltiazem (r(2) = 0.650; p = 0.005); however, C(2) correlated strongly with AUC(0-5) in patients receiving ketoconazole (r(2) = 0.870; p < 0.0001) or ketoconazole with diltiazem (r(2) = 0.898; p < 0.0001). C(0) was a poor predictor of AUC(0-5) in the latter 2 groups. CONCLUSIONS: C(2) showed a strong correlation with AUC(0-5) in cardiothoracic transplant recipients receiving CsA with ketoconazole, but not with CsA alone or diltiazem. TDM using C(2) as an estimate of AUC requires further evaluation before being applied in long-term, stable cardiac transplant patients, as it may lead to inappropriate dose adjustment of CsA in patients receiving concomitant metabolic inhibitors.     

C2 monitoring in maintenance renal transplant recipients: is it worthwhile?

Presently, there is little knowledge regarding cyclosporine (CsA) concentration at 2 hr post-dose (C2) monitoring in maintenance patients. This study evaluates the actual C2 range in stable renal transplant recipients (who underwent transplantation >12 months ago). In addition, we investigated whether underexposure or overexposure to CsA (assessed by C2) affects graft function (as measured by serum [S]-creatinine). All renal transplant recipients in Norway receiving CsA were asked to participate; 1447 fulfilled the criteria. Valid C2 and CsA trough concentration (C0) measurements were performed in 1032 renal transplant recipients (71%) monitored by C0. Target C0 level was 75 to 125 mumol/L. CsA levels were measured using a Cloned Enzyme Donor Immunoassay method, and all analyses were performed in the same laboratory (overall mean [+/-standard deviation] CsA C0=112+/-31 mug/L, CsA C2=697+/-211 mug/L [range 81-1580 mug/L], CsA dose [mg/day]=208+/-61, CsA dose [mg/kg/day]=2.8+/-1.1, and S-creatinine=141+/-58 mumol/L). A univariate analysis of variance showed that patients with C2 levels between 700 and 800 mug/L (n=203, S-creatinine=136+/-49 mumol/L) had significantly lower S-creatinine levels compared with patients with C2 levels greater than 950 mug/L (n=94, S-creatinine=152+/-56 mumol/L) (P<0.02). The same was true for patients with C2 levels less than 450 mug/L (n=95, S-creatinine 141+/-72 mumol/L) (P<0.05) when compared with patients with C2 levels greater than 950 mug/L. There was no significant difference in S-creatinine between patients in the low and intermediate C2 group; 666 patients had C0 levels in the therapeutic range (75-125 mumol/L). A linear regression showed a significant relation between S-creatinine and C2 for these patients (P=0.03). The corresponding relation between S-creatinine and C0 was nonsignificant (P=0.3). Monitoring of C2 in maintenance patients is a valuable tool to detect overexposure to CsA. Until results from prospective studies are available, we recommend C0 in the therapeutic range and reduction in CsA in overexposed patients, aiming at a C2 value between 700 and 800 mug/L.     

C2 is superior to C0 as predictor of renal toxicity and rejection risk profile in stable heart transplant recipients

To assess whether cyclosporine A (CsA) 2-h peak (C2) is superior to trough levels (C0) for Neoral dose monitoring in heart transplantation (HT), we studied 928 C0-C2 paired determinations from 313 stable HT patients (257 male, aged 50 +/- 14 years at HT, follow-up 6.9 +/- 4 years), on a C0-based regimen. Our target C0 levels (ng/ml) were 150-400 (first 3 months), 150-300 (4-12 months), 100-250 (>12 months). Mean C0 and C2 levels were 268 +/- 80 and 1031 +/- 386, respectively (first 3 months); 230 +/- 49 and 955 +/- 239 (4-12 months); 157 +/- 53 and 745 +/- 236 (>12 months). For patients within the target C0, the corresponding C2 were 600-1500 (first 3 months), 600-1300 (4-12 months), 400-1100 (>12 months). C2 correlated with C0 (r = 0.64, P = 0.0001). C2 correlated better with CsA dose than C0 (r = 0.41, P = 0.0001 vs. r = 0.33, P = 0.0001). Between patients, CsA dose varied by a factor of 9.3; the C/dose ratio varied by a factor of 8.5 for C2 and of 15.6 for C0. Patients with higher C2 (>740) had higher severe rejection score at 2 years (P = 0.02) than patients with lower C2. This did not apply to C0. Both C2 and C0 correlated with blood urea (r = -0.18, P = 0.0001; r = -0.12, P = 0.0002) and creatinine (r = -0.19, P = 0.0004; r = -0.19, P = 0.0001 respectively). By logistic regression higher C2 (>740) was associated with higher total severe rejection score at 2 years (P = 0.006). C2 showed better correlation with CsA dose, renal function, rejection profile and less variability between patients than C0. C2 may improve CsA-based immunosuppression in HT.     

Early cyclosporine C0 and C2 monitoring in de novo kidney transplant patients: a prospective randomized single-center pilot study

BACKGROUND: C2 monitoring of cyclosporine (CsA) has been promoted as improving the results of organ transplantation. No randomized, controlled studies in de novo kidney transplant recipients are available. METHODS: Between June 2003 and August 2004, 160 consecutive cadaveric kidney recipients allocated to CsA, mycophenolate and steroids were randomized to either C0 or C2 monitoring of CsA for the first 3 weeks posttransplant. Both levels were measured, keeping the other level blinded until 3 weeks. Altogether, 1451 double measurements were done. The target C0 was 200-300 microg/L and C2 1500-2000 microg/L. From the fourth week on, only C0 monitoring was used. Median follow up time was 505 days. RESULTS: The overall 3-month rejection rate was 7.5% in Group C0 vs. 10.8% in Group C2 and the one-year graft survival rates were 92.5% vs. 94.6% (NS). Rate of delayed graft function was similar in the groups. Plasma creatinine tended to be higher in group C2 at 3 weeks, but not thereafter. During the first three weeks posttransplant, the mean CsA dose was 57%, mean C2 levels were 55%, and mean C0 levels were 98% higher in group C2 than in group C0 (P < 0.00001). CONCLUSION: This pilot study showed no advantages of C2 monitoring but led to significantly higher CsA doses and blood levels than C0 monitoring.     

Comparison of cyclosporine concentrations 2 hours post-dose determined using 3 different methods and trough level in pediatric renal transplantation

Immunosuppression has been one of the great challenges in pediatric recipients of kidney allografts. Cyclosporine (CsA) has evolved during the past 25 years of transplantation. It requires frequent blood level monitoring because of its narrow therapeutic window and interpatient and intrapatient variability. Neoral (Novartis) is no exception. Ideally, monitoring of blood levels should also include determination of the area under the time-concentration curve (AUC) to better target the therapeutic window, thus avoiding underdosing or overdosing, especially in pediatric patients. A single blood concentration measurement 2 hours after Neoral administration (C2) has been shown to be a more for accurate predictor of drug exposure than trough levels (C0). Therefore, its use may lead to reduction in the incidence and severity of cellular rejection and of CsA toxicity. Some studies have shown that the metabolites/CsA ratio is substantially lower using C2 than C0, however, the between-assay differences for C2 monitoring have not been considered. The purpose of this study was to evaluate CsA C0 and C2 levels, determined using monoclonal fluorescence polarization immunoassay (FPIA)/TDx and enzyme multiplied immunoassay (EMIT). CsA levels were determined using a radioimmunoassay (RIA) in 30 pediatric transplant recipients with stable renal function within 42.7 mean months follow-up. Mean age was 13.4 years; 15 children were girls; 23 patients were recipients of cadaveric kidneys. The mean CsA microemulsion dose was 5.7 mg/kg/d. The 3 methods showed a high correlation between C0 and C2 (r > or = 0.97). A linear regression slope was significantly higher for C0 than C2 (P < .001). The CsA concentrations both at C0 and C2 were significantly higher with FPIA than with RIA (P < .009) but no differences were found for EMITT (P = .2). The mean C0 level for FPIA was 22% and 26% higher than RIA and EMIT, respectively. The mean C2, for FPIA was 7% and 12% higher than RIA and EMIT, respectively. In conclusion, CsA levels determined using RIA or EMIT are better than using FPIA/Tx; also, C2 CsA levels are more accurate than C0 in pediatric transplantation patients.     

Cyclosporine plasma levels six hours after oral administration. A useful tool for monitoring therapy

Clinical evolution and cyclosporine (CsA) monitoring of 65 transplanted patients (55 kidneys, and 10 kidneys and pancreases) treated with CsA were analyzed retrospectively (45 patients) and prospectively (34 patients). Our results showed the following: (1) nephrotoxicity is not uncommon even with low trough plasma levels of CsA; (2) the T6 value of a CsA pharmacokinetic plasma curve (6 hr after oral drug administration) is a valid expression of a full pharmacokinetic study; (3) when T6 was used prospectively as a monitoring tool and dose adjustments made disregarding concomitant serum creatinine levels, the latter decreased when CsA dose adjustments were made to correct toxic (greater than 350 ng/ml) or subtherapeutic (less than 100 ng/ml) T6, P less than 0.01. At present, serum creatinine for all our patients is 180.2 +/- 8 mumol/L, and no patient has needed to be switched to conventional treatment. The validity of trough plasma levels in patients under CsA oral administration once or twice a day seems questionable, and T6 proved to be more useful. Thus nephrotoxicity and CsA undertreatment may be avoided. This new monitoring tool (T6) will allow the utilization of lower doses of CsA and thus contribute to improved long-term graft function.