大黄制剂对肾移植受者环孢素血药浓度的影响分析

目的研究肾移植受者服用大黄制剂对环孢素血药浓度的影响。方法 2008年1月至2012年12月,湖州市第一人民医院10例肾移植受者术后采用环孢素＋吗替麦考酚酯/硫唑嘌呤＋泼尼松三联免疫抑制方案,环孢素用量为5~7 mg·kg-1·d-1,受者术后2~5年因便秘同时服用大黄苏打片（每片含大黄0.15 g,碳酸氢钠0.15 g）,3片/次,3次/d。服用当天及15 d监测受者环孢素血药浓度谷值（C0）、2h后血药浓度峰值（C2）以及肝肾功能,停药15d复查环孢素C0和C2。结果服用大黄苏打片15 d受者环孢素C0、C2均高于服用当天检测值,差异均有统计学意义（t=11.754和12.822,P均〈0.05）。停用大黄苏打片15 d复查环孢素C0、C2均低于服用15 d时检测值,差异均有统计学意义（t=10.020和13.596,P均〈0.05）;与服用当天检测值比较,差异均无统计学差异（t=1.375和0.251,P均〉0.05）。服用大黄苏打片15 d,受者肝肾功能指标与服用当天比较差异均无统计学差异（P均〉0.05）。结论肾移植术后服用环孢素的受者在长期使用含有大黄制剂的药物时,应注意监测环孢素血药浓度,必要时适当调整环孢素用量。     

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.     

Comparison of cyclosporine absorption profiles over a 12-month period in stable pediatric renal transplant recipients

Evidence suggests that the pharmacokinetic (PK) profile of microemulsion- cyclosporine A (m-CsA) during the 4-hour absorption phase represents an accurate tool to estimate drug exposure. In addition, several reports suggest a close correlation between selected single CsA concentrations at 1, 2, or 3 hours post-dose (C(1), C(2), and C(3)) and the abbreviated area under the curve (AUC)(0-4) among pediatric renal transplant patients. However, it is still unclear whether these PK correlations remain stable and reliable over 12 months posttransplant. In this study, we obtained 4-hour pharmacokinetic profiles (AUC(0-4)) from stable pediatric renal transplant recipients (phase 1) with repeat measurements 12 months later (phase 2). In addition, we evaluated the optimal single sampling point that correlated with the AUC(0-4) during both phases of the study.Over 1 year there was no significant change in the AUC(0-4) of m-CsA in pediatric renal transplant recipients. The mean dose-normalized AUC(0-4) values changed by less than 2.5%, namely, 557 versus 545 ng x h/mL per unit dose, respectively. The C(1) value was the sampling point that showed the best correlation with AUC(0-4); C(0) displayed the weakest correlation. No changes in cyclosporine dosing or glomerular filtration rate estimates were observed throughout the study period. This study demonstrates the stability of drug measurements during m-CsA therapy.     

Single daily dose administration of cyclosporine in renal transplant recipients

Cyclosporine (CsA) microemulsion has been the mainstay immunosuppressive agent for renal transplant recipients for years. A single daily dosing of cyclosporine (SD) is rarely used. The objective of this study was to evaluate the efficacy of SD versus twice daily dosing of CsA. Retrospective evaluation of SD use was conducted for 44 renal transplant recipients for 12 months (study group). Equal numbers of matched recipients were selected for age, sex, HLA mismatch, donor type, and immunosuppressive regimen (control group). We measured CsA trough (C0) and peak (C2) blood levels, 12-hour CsA profile, and the area under the concentration-time curve (AUC). There were significant differences in C0, C2, and calculated AUC after shifting to SD. In the study group, the mean AUC was 4619 ng/mL/h before versus 6567 ng/mL/h after shifting to SD (P=.004). This became more therapeutic and identical to the mean AUC in the control group, which was 6551 ng/mL/h. Total daily CsA dose was significantly lower in the study group compared with the control group (P<.0001). A significantly higher incidence of hepatitis was observed among the study group (P=.011). There were significantly fewer adverse effects in patients in the study group than the control group. There were no significant differences in graft and patient outcomes between the groups. We concluded that CsA dose should be individualized in renal transplant recipients especially if they have viral hepatitis. SD has the advantage of decreasing dosage and CsA-related adverse effects while maintaining optimal graft function.     

Randomized, International Study of Cyclosporine Microemulsion Absorption Profiling in Renal Transplantation with Basiliximab Immunoprophylaxis

Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (Neoral^TM) therapy, and that CsA exposure early post‐transplant may correlate significantly with reduced risk of acute graft rejection. This randomized, prospective, multicenter international concentration‐controlled study was conducted in 21 renal transplant centers in 8 countries to test and compare the clinical feasibility, functionality, accuracy, precision and prediction of rejection by cyclosporine microemulsion absorption profiling to conventional trough‐level drug monitoring. Primary or second renal allograft recipients treated with basiliximab, cyclosporine microemulsion and prednisone immunosuppression were randomized to two study groups in which cyclosporine microemulsion therapy was monitored using a multipointalgorithm or by trough levels. The two study arms were comparable in terms of baseline characteristics, treatment and clinical outcomes. Treatment failure, consisting of acute rejection, graft loss or death, occurred with equal incidence in the two groups (30% and 33%, respectively). Diagnostic feasibility, measured as the proportion of samples obtained within the designated time window, was marginally lower in area under the time‐concentration curve (AUC) than in trough groups, but the therapeutic accuracy and precision were comparable or superior in the AUC group. Cox regression analysis performed across study groups showed a highly significant correlation between the predicted probability of acute rejection and cyclosporine (CsA) exposure measured by AUC over the entire 12‐h dosage interval (AUC[0–12]) (p = 0.0068), AUC over the first 4 h of the 12‐h dosage interval (AUC[0–4]) (p = 0.0014) or 2 h post‐dose (C2) CsA level (p = 0.0027). Day 3 dose‐ and weight‐corrected C2 values (EMIT equivalent) separated patients into low (< 200 μg/L/mg/kg dose), intermediate (200–350 μg/L/mg/kg dose) and high absorber categories (> 350 μg/L/mg/kg dose), defining those at greatest risk. Within these categories, C2 values above approximately 1500 μg/L by day 3 post‐transplant were associated with the lowest predicted probability of rejection. Comparable analysis by Cox regression using C0 levels did notreach statistical significance. Absorption profiling is a feasible, accurate and precise method for monitoring cyclosporine microemulsion therapy in clinical practice and, as shown in the companion article, may be simplified by the use of single‐point C2 concentrations which accurately predict individual AUC[0–4] exposure levels. Both cyclosporine microemulsion relative absorption (i.e. dose‐ and weight‐corrected exposure) and CsA exposure (measured by predicted AUC or C2 levels) are closely correlated with the risk of rejection, and define patients at high and low risk of acute graft rejection. Trough (C0) levels are not closely correlated with either CsA exposure or rejection risk, and should not be considered reliable for monitoring cyclosporine microemulsion therapy.     

Basiliximab-chimeric anti-IL2-R monoclonal antibody in pediatric liver transplantation: comparative study

Basiliximab is a monoclonal antibody that binds to the alpha subunit (CD(25)) of the interleukin-2 receptor of activated T lymphocytes. The advantage of basiliximab in organ transplantation is the reduce possibility to calcineurin inhibitor dosages to avoid nephrotoxicity. Basiliximab has significantly reduced the incidence of acute rejection (AR) in renal transplant recipients; however, the results are uncertain in liver transplantation (LT). The objective of this investigation was to assess the effect of basiliximab to prevent AR in the first 6 months after pediatric LT. From March 2000 to October 2001, 32 recipients of a primary orthotopic cadaveric or living donor LT were given basiliximab by intravenous bolus injection on the day of transplantation (day 0) and on day 4. Four children who received one dose were excluded from the study. The rate and the intensity of AR episodes, the incidence of chronic rejection, serum creatinine level, incidence of infections, adverse side effects, and daily oral dosage of cyclosporine (Neoral) to maintain the target blood level of 850 to 1000 mg/dL at C2, 2 hours after the administration, were analyzed in the remaining 28 recipients. Results were compared to those obtained from a matched historical group (n = 28) of similar age, weight, and hepatic diseases distribution. None of the analyzed parameters was statistically significant (P >.05) except for the daily oral dose of cyclosporine (7 to 13 mg/kg/dose, P <.05). In our series, the addition of basiliximab to the immunosuppressive therapy did not reduce the incidence of AR in pediatric LT.     

Pharmacokinetics of mycophenolate mofetil in stable pediatric liver transplant recipients receiving mycophenolate mofetil and cyclosporine.

There are few pharmacokinetic data for mycophenolate mofetil (MMF) when used in combination with cyclosporine (CsA) in pediatric liver transplant recipients. The aim of this study was to assess the pharmacokinetics of MMF in stable pediatric liver transplant patients and estimate the dose of MMF required to provide a mycophenolic acid (MPA) exposure similar to that observed in adult liver transplant recipients receiving the recommended dose of MMF (target area under the plasma concentration-time curve from 0 to 12 hours [AUC(0-12)] for MPA of 29 mug.hour/mL in the immediate posttransplantation period and 58 microg x hour/mL after 6 months). A 12-hour pharmacokinetic profile was collected for 8 pediatric patients (mean age 20.9 months) on stable doses of MMF and CsA who had received a liver transplant > or = 6 months prior to entry and who had started on MMF within 2 weeks of transplantation. Mean MMF dosage was 285 mg/m(2) (range, 200-424 mg/m(2)). Of 8 patients, 7 had a MPA AUC(0-12) (range, 11.0-37.2 microg x hour/mL) well below the target. One patient had an AUC(0-12) > or = 58 microg x hour/mL but was considered an outlier and was excluded from analyses. Mean MPA AUC(0-12) and maximum plasma concentration values were 22.7 +/- 10.5 microg x hour/mL and 7.23 +/- 3.27 microg/mL, respectively; values normalized to 600 mg/m(2) (the approved pediatric dose in renal transplantation) were 47.0 +/- 21.8 microg x hour/mL and 14.5 +/- 4.21 microg/mL. In conclusion, assuming that MPA exhibits linear pharmacokinetics, when used in combination with CsA, a MMF dose of 740 mg/m(2) twice daily would be recommended in pediatric liver transplant recipients to achieve MPA exposures similar to those observed in adult liver transplant recipients. This finding should be confirmed by a prospective trial.     

Evaluation of cyclosporine C2 levels in long-term stable renal allograft recipients

BACKGROUND: The use of cyclosporine was traditionally monitored by the trough level (C(0)). However, the immunosuppressive effects of cyclosporine correlate with its drug exposure, represented by the area under curve (AUC). It was also noted that cyclosporine C(0) level correlated with AUC poorly, while C(2) level (concentration at 2 hours after drug administration) satisfactorily correlated with AUC. Most recent studies concern the use of C(2) levels in de novo renal transplant patients; target levels of C(2) have been suggested. There is rare discussion about the C(2) target level for long-term cyclosporine-maintenance patients. Our objectives were to analyze the cyclosporine C(2) levels of patients more than 12 months after transplantation as well as changes in C(2) with time and the correlation between C(2) level and renal function. METHODS AND PATIENTS: This was a cross-sectional case-controlled study of 101 kidney recipients immunosuppressed with a cyclosporine-based regimen for at least 12 months. Both C(0) and C(2) levels were examined at various time points during outpatient clinic follow-up. The patients were stratified according to the time after transplant surgery, or to their renal function. RESULTS: The 101 patients were divided into three groups based on the time after renal transplant surgery. Groups 1, 2, and 3 represented patients transplanted for 1 to 3 years (n = 16), 4 to 6 years (n = 35), and more than 6 years (n = 50), respectively. The C(2) levels for each group were 657 +/- 232, 561 +/- 186, and 580 +/- 243 ng/mL, respectively, (P = NS). When stratified into low versus high C(2) groups, there were no significant differences in renal function both at the beginning and at the end of 1 year follow-up. Seven of 67 patients shifted to stronger immunosuppression in the low C(2) group, but only 2/34 in the high C(2) group, a difference that was not significant (P = .234 by Fisher Exact Test). Patients with creatinine levels greater than 1.5 mg/dL or lower than 1.5 mg/dL showed no difference in C(2) on C(0) levels. Patients with deterioration of renal function during this period had no different C(2) levels as those with no deterioration of renal function. CONCLUSION: The average C(2) levels among long-term cyclosporine-maintained patients were significantly lower than those previously suggested. C(2) levels did not correlate with the long-term outcome of renal function in patients at least 1 year after renal transplantation.     

Single daily dose administration of cyclosporine in renal transplant recipients: a preliminary report

INTRODUCTION: Cyclosporine microemulsion has been the mainstay immunosuppressive agent in renal transplantation for years. Since single daily dosing of cyclosporine is rarely used, the objective of this investigation was to evaluate the efficacy of a single daily dose versus twice daily dosing of cyclosporine in renal transplant recipients. METHODS: Retrospective evaluation of single-dose cyclosporine use was conducted for 15 renal transplant recipients for 12 months (study group). Equal numbers of matched renal transplant recipients were selected for age, sex, human leukocyte antigen mismatch, donor type, and immunosuppressive regimen (control group). Cyclosporine trough level and peak cyclosporine blood levels, 12-hour cyclosporine profile, and the area under the concentration-time curve were measured. RESULTS: There was a significant difference in cyclosporine peak blood level and calculated area under the curve after shifting to single-dose cyclosporine (P = .001). In the study group, the mean area under the curve was significantly below the average therapeutic range before (3154 ng/mL/ho) versus 5532 ng/mL/h after shifting to the single-dose regimen (which was therapeutic). This value was 5749 ng/mL/h in the control group. Total daily cyclosporine dose was lower in the study group when compared with the control group at 6 and 12 months (P = .01). There were significantly fewer adverse effects in patients in the study group than in patients in the control group. CONCLUSION: We conclude that although cyclosporine dose should be individualized in renal transplant recipients, a single dose of cyclosporine has the added advantage of decreasing dosages and cyclosporine-related adverse effects while maintaining optimal graft function.     

The factors affecting blood pressure in pediatric renal transplant recipients

To investigate the parameters affecting systemic blood pressure in pediatric renal transplant recipients, we retrospectively examined the data from 19 adolescent renal transplant recipients including 6 girls overall, mean age of 15,47 +/- 3.56 years. Serum creatinine (Scr), fractional extraction of sodium (FENa), whole blood trough cyclosporine(C0), plasma total cholesterol (TC) and triglyceride levels, and systolic and diastolic blood pressure (SBP and DBP) were monitored during a total of 677 visits. SBP and DBP, classified as <95p (groups 1s and 1d) and >95p (groups 2s and 2d), were correlated with differences between groups 1 and 2. Group 2s Scr and FENa levels were higher than group 1s (P =.002 and P =.048, respectively), whereas C0 and FENa levels were higher in Group 2d than Group 1d (P = 0.028 and P = 0.036, respectively). Among the entire group, SBP and DBP positively correlated with C0; Scr and SBP, with FENa. While there was a positive correlation between SBP and C0 in groups 1s and 2s (r = 0.188, P <.000; and r = 0.145, P =.040), DBP was only associated with C0 in group 1d (P =.03, r = 0.156). In contrast, DBP showed a positive correlation with Scr in group 2d (P =.023, r = 0.132), and SBP with Scr in Group 1s. C0 and Scr levels were correlated in Groups 1s, 1d and 2d. At high BP levels (>95p), SBP is mostly affected by C0; DBP, with Scr. However, in both groups these two parameters positively correlate with each other. Thus, in adolescent renal transplant recipients the cause of high blood pressure does not appear to be solely related to cyclosporine related to induced allograft dysfunction.     

Assessment of cyclosporine therapeutic monitoring with C2 concentrations in stable renal allograft recipients

The optimal long-term C2 target to minimize the risk of chronic allograft nephropathy (CAN) has not yet been established in a prospective study. Furthermore, it is not known whether the target is the same in patients who also receive mycophenolate mofetil (MMF). We determined the 2-hour postdose concentration (C2) in a cohort of 65 maintenance renal transplant patients. The mean C0 level was 0.12 microg/mL and the C2 was 0.62 microg/mL. The overexposed patients are 14%. There was a good correlation between C0 and C2, and between C2 and the cyclosporine (CsA) dose. Patients receiving MMF display lower levels of C0 and C2, lower dosages of CsA, and higher levels of plasma creatinines. We did not observe significant differences on relating the level of absorption to patient age and sex, creatinine level, CsA dose, or coadministration of MMF. In conclusion, there is a low incidence of overexposed patients. C2 levels of approximately 0.6 microg/mL (and possibly may be sufficient in renal transplant patients. somewhat lower [0.5 microg/mL] in patients receiving MMF) Patients who display slow or fast absorption of CsA do not have any apparent characteristic.     

No gender-associated differences of cyclosporine pharmacokinetics in stable renal transplant patients treated with diltiazem

Cytochrome-P450 enzymes metabolize cyclosporine both in the liver and in the intestinal wall. Diltiazem, by competitive inhibition of these enzymes, may increase the absorption and the bioavailability of cyclosporine. Some evidence points to a higher activity of some specific enzymes in women, such as CYP3A, that may influence differences in cyclosporine pharmacokinetics. We examined possible gender-associated differences in pharmacokinetic profiles of cyclosporine in 19 stable renal transplant recipients cotreated with diltiazem. Ten women and nine men, chronically using diltiazem associated with cyclosporine, azathioprine, and prednisone were randomly assigned to an 8-week period of continued controlled treatment with diltiazem (10 patients) or a wash-out period discontinuing diltiazem (nine patients). At the end of this period, the time-concentration curves of cyclosporine in the first 4 hours were performed after a single dose of cyclosporine. Thereafter, a cross-over between groups was performed, and time-concentration curves repeated. A specific RIA was used to measure cyclosporine concentrations. Comparisons between male and female patients in doses of cyclosporine and other pharmacokinetics parameters (C(0), C(2), AUC(0-4)), with or without diltiazem, did not show any difference related to gender. The association of diltiazem allowed a similar degree of reduction in Neoral dosage in male and female patients (21%). No changes in serum creatinine, blood urea nitrogen, potassium, uric acid, or blood pressure, or other adverse event were observed during the study. In these groups of patients, gender was not an important factor to be considered when diltiazem is added to cyclosporine therapy.     

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.     

Calcineurin inhibitor reduction based on maintenance immunosuppression with mycophenolate mofetil in renal transplant patients: POP study

Since calcineurin inhibitors (CNI) have been introduced, they have become the cornerstone of immunosuppression for renal transplant patients, but their cardiovascular and neurological toxicities, and primarily their renal toxicity, have brought about an increased effort to find combinations of immunosuppressants that are either CNI-free or that use minimum doses of these drugs. The weight of immunosuppression therefore lies with drugs that have a better toxicity profile. The POP observational transverse study including 213 renal transplant patients was designed to study CNI minimization strategies. The mean time of transplant evolution to the time of reduction was 9.9 +/- 11.8 months. The acute rejection rate to the start of reduction was 9.4%. Almost all the patients were undergoing treatment with CNI + mycophenolate mofetil (MMF) + steroids in the immediate posttransplantation period. When reduction was chosen, all patients were undergoing treatment with MMF (mean dose at the start of reduction = 1490.7 +/- 478.0 mg/d). Among the cohort, 66.7% of patients were being treated with tacrolimus (mean C0 levels 13.3 +/- 6.6 ng/mL) and 33.3% with cyclosporine (mean C0 levels 192.2 +/- 94.0 ng/mL; mean C2 levels 1097.5 +/- 457.6). The main reasons for withdrawal were nephrotoxicity (55.9% of the cases), as well as prevention of adverse effects (21.6%). The mean target CNI dose reduction was 41.4% +/- 21.45% in the tacrolimus group and 28.6 +/- 10.0% in the cyclosporine group. In conclusion, CNI toxicity, primarily renal toxicity, makes reduction of these drugs based on the use of full MMF doses an alternative to manage renal transplant patients.     

The clinical benefits of cyclosporine C2-level monitoring: a systematic review

BACKGROUND: Monitoring of cyclosporine microemulsion (Neoral) using 2-hour postdose (C2) levels is alleged to improve clinical outcomes, but the efficacy of this strategy is uncertain. METHODS: A systematic literature search was performed for trials directly comparing patients monitored with C2 levels with those monitored by trough (C0) levels. Primary outcomes assessed were renal function and acute rejection. RESULTS: A total of 29 studies met the inclusion criteria. Only 10 of these were randomized controlled trials. Overall quality was poor and this precluded meta-analysis. The most consistent finding in de novo renal, hepatic, and cardiac transplant recipients is a higher mean cyclosporine dose in the early postoperative period in C2 monitored patients. There is no clear evidence that this leads to impaired renal function. In the majority of studies, the monitoring strategy had no significant effect on the rate of acute rejection. In stable transplant recipients, the majority of studies show a reduction in mean cyclosporine dose with adoption of C2 monitoring. No obvious clinical benefit was derived from this reduction in dose. CONCLUSION: In de novo transplant patients, there is little evidence from prospective studies to support the theoretical benefits of C2 monitoring. Potential dose reductions in stable patients may reduce costs, but no short-term clinical benefit is seen. Quality of studies in this area is poor, and the practical limitations of C2 monitoring mean that further evidence is required before a strategy for the administration of cyclosporine based on C2 levels can be recommended.     

The area under the concentration-time curve versus trough and peak blood level monitoring in renal transplant recipients on cyclosporine

OBJECTIVE: The area under the concentration-time curve of cyclosporine microemulsion is the best measure of the absorption and beneficial effects in renal transplant recipients. We sought to determine the best method of monitoring cyclosporine levels in these patients. METHODS: Prospective evaluation of peak cyclosporine blood levels and area under the curve monitoring were performed for 1 year in 65 renal transplant recipients (study group). Cyclosporine trough levels and peak cyclosporine blood levels were correlated with the calculated area under the curve. Cyclosporine trough levels were monitored in equal numbers of matched controls. RESULTS: There were no significant differences in the incidence of acute rejection, cyclosporine nephrotoxicity, proteinuria, serum creatinine levels, or graft and patient outcomes between the groups (P = .1). Peak cyclosporine blood levels guided by calculating the area under the curve were found to be 27% to 32% lower than previously reported. The correlation coefficient was <70% for cyclosporine trough levels (P < .02) and >90% for peak cyclosporine blood levels (P < .001) when related to the calculated area under the curve. The calculated area under the curve was approximately 6000 ng/mL/h following transplantation, gradually decreasing to approximately 3000 ng/mL/h at 1 year. Both appeared to the acceptable therapeutic values. CONCLUSION: Calculating the area under the curve using trough and peak blood levels versus using isolated readings for either of these levels alone is the most effective method of monitoring cyclosporine in recipients undergoing renal transplant.     

The relative importance of cyclosporine exposure in heart,kidney or liver transplant recipients on maintenance therapy

We investigated the relationship between cyclosporine exposure and the presence of cyclosporine-related side effects and assessed the advantage of the cyclosporine concentration 2 h post-dose (C₂) over pre-dose concentration (C₀) monitoring. Cyclosporine area-under-the-concentration–time curves were measured during the absorption phase (AUC_{0–4 h}) in 49 liver, 28 heart and 26 kidney transplant recipients (time since transplantation >6 years) with or without cyclosporine-related side effects on maintenance therapy. The cyclosporine C₀ correlated well with AUC_0–4 (r=0.77), whereas C₂ levels correlated strongly with AUC_0–4 (r=0.92). Although we observed a trend towards higher CsA concentrations in transplant recipients with side effects than in patients without CsA toxicity, the large majority of those differences were not statistically significant. Thus, as cyclosporine exposure was not clearly related to the presence of side effects, and C₀ correlated fairly with AUC_0–4, the advantage of monitoring cyclosporine treatment using C₂ rather than C₀, may be limited for patients on cyclosporine maintenance therapy.     

Evaluation of performance factors affecting two formulations of cyclosporine in pediatric renal transplant patients

Success of renal transplantation in children is largely due to improvements in immunosuppressant therapy since the introduction of calcineurin inhibitors. The aim of this study was to identify possible factors that result in formulation differences in the exposure of pediatric patients to cyclosporine (CsA). We examined the handling of the two major formulations of CsA in a group of pediatric renal transplant recipients. The pharmacokinetic profiles of both formulations were assessed, and the data stratified to assess the effects of age, gender, time posttransplant, and other concomitant drug therapy on the two CsA formulations. The microemulsified formulation (MEC) enhanced bioavailability compared to the older oil-based formulation (CYA), especially at C2, with more predictable and consistent absorption in children. This higher bioavailability allowed a 15% reduction of dosing to achieve equal drug exposure. The concentration achieved by MEC at C2 demonstrated a much higher correlation with area under the concentration curve (AUC) than the concentration at C0. In the case of CYA a strong correlation was obtained between AUC and the concentrations obtained at both C0 and C2. Calcium channel blockers increased AUC(0-8) for both CsA formulations. Norfloxacin and pravastatin cotreatment had no effect on either of the CsA formulations. In contrast, the bioavailability of CsA was increased in boys using MEC formulation but this gender-based difference was absent during the use of CYA. This suggests that caution is required for introduction of new formulations of drugs to pediatric patients to evaluate differential effects of age, gender, and concomitant drug therapy.     

C2 and C0 values for monitoring cyclosporine therapy in stable heart transplant recipients

INTRODUCTION: We sought to evaluate the behavior of C2 values and their correlation with acute rejection episodes and cyclosporine (CyA) side effects in heart transplant patients whose immunosuppressive therapy, was monitored with C0 trough levels. METHODS: Sixty stable patients who had received heart transplants from 3 months to 60 months prior were randomly observed from September 2001 to June 2004. Four area under the concentration-time curves (AUC) were performed on each patient, a total of 240 AUC curves. RESULTS: Regarding the variability of CyA absorption, two groups of patients were distinguished: group A, "constant absorbers," namely, low variability (<15%) of CyA absorption; group B, "inconstant absorbers" patients with higher (>15%) variability of absorption. Group B patients showed more acute rejection episodes (41%) than group A (19%). CyA side effects were more serious in patients with higher variability of absorption: systemic hypertension, neurological disorders, hyperlipidemia, and gum hyperplasia; Group B patients who developed CyA side effects showed higher maximum and mean C2 levels (P < .05) than group A patients. No differences were found with regard to renal dysfunction between the two groups: all patients showed a mean increase of serum creatinine by at least 50% compared to the baseline value. CONCLUSION: Higher C2 levels were not sufficient to predict acute rejection compared to lower but constants, C2 levels. Patients with inconstant absorption were more often overexposed to CyA than underexposed, developing more side effects than patients with lower variability of absorption. Monitoring CyA therapy with C0 and C2 may prevent over- or underexposure to the drug.     

Cyclosporine monitoring in stable, long-term, pediatric kidney transplant recipients: the value of C2 determination

Although a generalized consensus has been reached for therapeutic drug monitoring of cyclosporine microemulsion in adult transplant patients, clear guidelines are recently not available for the pediatric population. In this retrospective analysis of pharmacokinetic data obtained from stable, long-term, pediatric kidney transplant recipients, we sought to define a possible approach to manage cyclosporine therapy in a pediatric setting. The 2-hour postdose cyclosporine blood concentration, C(2), rather than trough levels, was the best single time point predictor of the area under the concentration curve. We concluded that therapeutic drug monitoring of cyclosporine-based immunosuppressive regimens should be tailored based on C(2) determinations for pediatric kidney transplant recipients.