Interaction between cyclosporine and fluconazole in renal allograft recipients

To determine the effect of fluconazole on cyclosporine concentrations, we used a randomized, double-blind, placebo-controlled study design to evaluate 16 stable renal transplant recipients receiving a constant cyclosporine dose. The two groups of patients were given identical capsules of either placebo or fluconazole 200 mg daily for 14 days. Compliance with the protocol was ensured by watching each patient take all the drug doses. Frequent whole-blood cyclosporine trough concentrations, measured by high-performance liquid chromatography, and two area under the blood concentration time curves were determined before and after 14 days of fluconazole or placebo. The results show that cyclosporine trough concentrations, in patients given fluconazole, increased from a mean +/- SD of 27 +/- 16 to 58 +/- 28 ng/ml (P = 0.001) while patients given placebo did not change--35 +/- 26 vs. 37 +/- 35 ng/ml (P = 0.7). Mean cyclosporine AUC increased in the fluconazole patients from 2167 +/- 1039 to 3989 +/- 1675 ng.hr/ml (P = 0.02) while the placebo patients did not change, 3089 +/- 2439 vs. 2954 +/- 2216 ng.hr/ml (P = 0.9). The pre- and post-treatment cyclosporine AUC difference (day 16 minus day 2) for fluconazole vs. placebo was 1822 +/- 1083 vs. -134 +/- 831 ng.hr/ml (P = 0.001). Mean cyclosporine clearance decreased an average of 55% in the fluconazole patients from 1.2 +/- 0.5 to 0.7 +/- 0.4 ml/hr.kg (P = 0.03); the placebo patients did not change--1.4 +/- 1.1 vs. 1.7 +/- 2.3 ml/hr.kg (P = 0.07). During the study period, serum creatinine concentrations did not increase after fluconazole vs. placebo treatment; they were 1.4 +/- 0.3 vs. 1.3 +/- 0.3 mg% (P = 0.8) initially, and 1.4 +/- 0.2 vs. 1.3 +/- 0.3 mg% (P = 0.5) after 14 days. This study indicates that fluconazole 200 mg daily can slowly increase cyclosporine concentrations over two weeks of therapy, approximately doubling the cyclosporine trough concentrations. The management of this interaction requires prospective planning for adjustments in the cyclosporine dosage, guided by cyclosporine concentrations, while transplant recipients are receiving fluconazole.     

Pharmacokinetics and nephrotoxicity of cyclosporine in renal transplant recipients

Pharmacokinetics of Cyclosporine (CsA) were studied in 14 renal transplant patients during a three-month period of treatment. At 3 and 15 days after transplantation 12-hr blood level studies of the drug were performed to calculate the elimination half-life, area under the curve (AUC), and total blood clearance; trough levels were measured twice weekly. In 9 patients terminal half-lives could be calculated after discontinuation of CsA treatment. In the course of CsA treatment, prolongation of half-life was found in most cases, with a significant decrease in clearance (46 +/- 17 L/hr on day 3 versus 28 +/- 10 L/hr on day 15). This resulted in a continuous increase in the CsA blood level. The terminal half-life varied considerably among the patients (24-93 hr) and did not correlate with other pharmacokinetic parameters. A good correlation (r = 0.9589) was observed between CsA trough levels before discontinuation of CsA and the increment in renal function two weeks after conversion to azathioprine. This indicates that short-term CsA treatment induces a dose-dependent reversible nephrotoxic effect in renal transplant recipients.     

Conversion from cyclosporine to azathioprine in renal allograft recipients

Fifty seven recipients of renal allografts initially treated with CsA and low-dose prednisone were switched to azathioprine and low-dose steroids. Ten had prolonged (greater than 28 days) allograft nonfunction after transplantation (group 1), 8 had ongoing, poorly controlled rejection (group 2), and 39 had stable functioning grafts (group 3). With a mean follow-up period of 5 +/- 3 months after conversion, 50 grafts remained functional including 6 of 10 in group 1, 6 of 8 in group 2, and 38 of 39 in group 3. Thirty-seven (65%) had improved function, 12 (21%) had stable function, and 8 (14%) experienced declining renal function. Three of these latter 8 patients required reinstitution of CsA therapy. There were 20 episodes of acute rejection in 18 patients; one graft lost function because of acute rejection unresponsive to therapy. Reasons for the 6 other graft losses were persistent primary nonfunction in 3 patients from group 1, untreated rejection in 2 patients who had multiple prior rejection episodes while on CsA, and chronic rejection in one patient. Although renal function has improved or stabilized in the majority (86%) of individuals changed to azathioprine therapy, there was substantial risk of acute rejection (32%) complicating this procedure. Patients most likely to benefit from conversion to azathioprine therapy are those with prolonged graft nonfunction after transplantation and those with serum creatinines greater than 2.0 mg/dl.     

Conversion of stable renal allograft recipients to a bioequivalent cyclosporine formulation

BACKGROUND: Gengraf capsule, an AB-rated generic cyclosporine for Neoral, has been shown to be bioequivalent in previous studies. The purpose of this pharmacokinetic study performed in stable renal transplant recipients was to evaluate interchangeability of Gengraf and Neoral. METHODS: Using an open-label, three-period design, 50 renal transplant recipients taking stable doses of Neoral completed a multicenter study. Subjects continued their Neoral regimen during period I (days 1-14). Subjects then switched from Neoral on a milligram-for-milligram basis to Gengraf during period II (days 15-28), followed by conversion to the same milligram-for-milligram dosing regimen of Neoral during period III (days 29-35). Twelve-hour pharmacokinetic evaluations (maximum observed blood concentration [C(max) ], concentration before dosing [C(trough) ], time to maximum observed concentration [T(max) ], and area under the blood concentration-vs.-time curve [AUC]) occurred on days 1, 14, 15, 28, and 29. Additional predose samples (C (trough)) were evaluated on days 7, 21, and 35. Laboratory and safety parameters were also evaluated. RESULTS: The pharmacokinetics of Gengraf (C(max), T(max), C(trough), and AUC) were indistinguishable from the Neoral values in stable renal allograft recipients. The bioequivalent capsules were interchangeable with respect to C(max), C(trough), and AUC at steady state and also on conversion from one capsule formulation to the other. The 90% confidence intervals (CI) for the Gengraf versus Neoral comparison at steady state (day 28 vs. day 14) were 0.95 to 1.03 for AUC and 0.92 to 1.04 for C(max). Trough concentrations remained consistent throughout the study, with no need for dosage adjustment in any of the subjects. Gengraf is well tolerated, with an excellent safety profile, comparable to the safety profile of Neoral. CONCLUSIONS The pharmacokinetics of Gengraf are equivalent and indistinguishable from those of Neoral. Gengraf is well tolerated and interchangeable with Neoral in stable renal transplant recipients.     

肾移植术后撤除环孢素A的观察和体会

目的 总结肾移植术后因某些原因而撤除环孢素Ａ（ＣｓＡ）的经验教训,并对其可行性及安全性进行评价。方法 总结２０例术后撤除ＣｓＡ的肾移植患者的有关资料。结果 ２０例患者在撤除ＣｓＡ并同时调整其它免疫抑制剂剂量后,其肾功能、肝功能及白细胞计数等与撤药前比较,差异均无显著性;与周期常规治疗者比较,两组肾功能的差异也无显著性。结论 在调整其它免疫抑制剂剂量的前提下,逐步减少ＣｓＡ的用量并最终撤除ＣｓＡ,可     

T-lymphocyte subsets in renal allograft recipients treated with cyclosporine and azathioprine

Thirty-nine renal allograft recipients were prospectively studied to determine the quantitative effects of different immunosuppression protocols on T-cell subsets (total lymphocytes [T3], helper/inducer [T4] and suppressor/cytotoxic [T8]). Eighteen patients were initially immunosuppressed with only azathioprine and prednisone but required subsequent treatment for rejection by the addition of antithymocyte globulin (ATG) (Upjohn, Kalamazoo, MI) or conversion to cyclosporine. Three of these patients had ATG-resistant rejections and were treated with the monoclonal antibody ORTHO OKT3 (ORTHO Pharmaceuticals, Raritan, NJ). Twenty-one patients were treated only with cyclosporine and prednisone. Plasma levels of cyclosporine, as determined by high-performance liquid chromatography, were kept in the range of 50-100 ng/mL (mean: 78.1 +/- 52.1). One patient had a lymphoma, two patients had failed grafts, and three patients converted their cytomegalovirus titers. The results demonstrate that the immunosuppressive agents, azathioprine, prednisone, and cyclosporine, have an additive effect in depressing the T-lymphocytes and their subsets. In addition, ATG and cyclosporine had a more selective ablation of the T4 subset, resulting in a reversal of the T4/T8 ratios. This depression was independent of the plasma level of cyclosporine. Finally, the pan T-cell monoclonal antibody OKT3 led to severe depletion of all T-cell subsets but resulted in a normal T4/T8 ratio. In conclusion, immunosuppressive agents have a variable effect on T-lymphocytes and their subsets that cannot be adequately characterized by the T4/T8 ratio alone, but which should be quantitatively assessed by examining all subsets.     

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.     

Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients

BACKGROUND: Campath 1H is a depleting, humanized anti-CD52 monoclonal antibody that has now been used in 31 renal allograft recipients. The results have been very encouraging and are presented herein. METHODS: Campath 1H was administered, intravenously, in a dose of 20 mg, on day 0 and day 1 after renal transplant. Low-dose cyclosporine (Neoral) was then initiated at 72 hr after transplant. These patients were maintained on low-dose monotherapy with cyclosporine. RESULTS: At present, the mean follow-up is 21 months (range: 15-28 months). All but one patient are alive and 29 have intact functioning grafts. There have been six separate episodes of steroid-responsive rejection. One patient has had a recurrence of her original disease. Two patients have suffered from opportunistic infections, which responded to therapy. One patient has died secondary to ischemic cardiac failure. CONCLUSIONS: Campath 1H has resulted in acceptable outcomes in this group of renal allograft recipients. This novel therapy is of equal efficacy compared to conventional triple therapy, but allows the patient to be steroid-free and to be maintained on very-low-dose immunosuppressive monotherapy.     

发生慢性移植肾功能不全者以西罗莫司替换环孢素A的临床疗效

目的 对采用以环孢素A(CsA)为基础免疫抑制剂的慢性移植肾功能不全(CRAD)患者,将CsA转换为西罗莫司(SRL),观察转换后的临床效果和安全性.方法 20例肾移植后出现CRAD的患者,采用突然转换法将CsA替换为SRL(3 mg/d),霉酚酸酯(MMF)和泼尼松(Pred)的剂量维持不变.另随机选取9例仍然使用CsA、MMF和Pred的CRAD患者作为对照.观察血肌酐(Cr)、肾小球滤过率(GFR)和24 h尿蛋白定量的变化情况以及SRL的不良反应.结果 对照组与转换组在患者年龄、性别构成比、移植后时间、转换时的血Cr水平和转换时免疫抑制剂用量等方面的差异均无统计学意义.随访1年,转换组有18例完成观察,其中11例(61.1%,11/18)转换有效,7例(38.9%,1/18)转换无效.转换有效者和转化无效者在转换时的血Cr、移植后时间、GFR及24 h尿蛋白定量等方面的差异有统计学意义.转换有效者的血Cr明显下降,GFR明显升高,而转换无效者的血Cr呈进行性升高,GFR呈进行性下降.转换治疗期间,1例出现急性排斥反应,经冲击治疗后逆转.完成随访的18例中,2例发生感染,3例出现皮疹,3例出现腹泻,2例出现口腔溃疡,8例出现骨髓抑制,6例转氨酶升高,10例出现高血脂,4例出现低血钾,没有患者因为上述不良反应而退出观察.结论 肾移植后采用以CsA为基础的免疫抑制方案者,若出现CRAD,可以将CsA替换为SRL,部分患者的肾功能得到改善,但转换应在移植肾功能发生严重损害前进行.     

Effects of combination cyclosporine/mizoribine immunosuppression on canine renal allograft recipients

Heterotopic renal allografts following bilateral nephrectomies were placed in 21 healthy mongrel dogs. One group of 11 dogs received cyclosporine (5 mg/kg/24 hr, orally), and 1 group of 10 dogs received cyclosporine and mizoribine (5 mg/kg and 3 mg/kg/24 hr, orally). Body weights, blood cell counts, serum chemistry profiles, serum electrolyte levels, urinalysis with cytology and culture, lymphocyte stimulation assays, immunoglobulin levels, whole blood levels of cyclosporine, and serum levels of mizoribine were followed. At the end of each survival period, necropsy and histopathologic examinations were performed. The mean survival time for the cyclosporine group was 12.8 +/- 7 days. The mean survival time for the cyclosporine/mizoribine group was 33.6 +/- 16.4 days, significantly longer (P = .0006) than the cyclosporine group. Death in the cyclosporine/mizoribine group was attributed to the combined effects of renal allograft rejection and development of a mizoribine-dependent enteritis. Serum levels of mizoribine were greater in the last half of the survival period due to compromised renal excretion of the drug. There were no complications due to infection, myelosuppression, or hepatotoxicity. Combination cyclosporine/mizoribine immunosuppression enhanced canine renal allograft survival in this study. Monitoring serum concentrations of mizoribine is imperative to determine toxic (enteritis) levels. Availability of an intravenous form of mizoribine would facilitate immunoregulation during periods of variable intestinal absorption or renal excretion.     

Effect of cyclosporine A on long-term allograft function in pediatric renal transplant recipients

There have been concerns regarding long-term adverse effects of cyclosporine A (CSA) on renal allograft function. In a retrospective study, we compared long-term allograft function up to 70 months after renal transplantation in pediatric recipients treated with and without CSA, using iothalamate clearance to assess glomerular filtration rate. Patients received CSA, prednisone, and azathioprine (CSA group,n=16) or prednisone and azathioprine alone (Pred/AZA,n=11). At 48 months post transplant, the iothalamate clearances (mean±SD) were 57.9±26.8 ml/min per 1.73 m² in the CSA group and 68.5±20.2 in the Pred/AZA group (P>0.05). The mean of the slopes of individual iothalamate clearances versus time during the first 70 months following transplantation were –0.156 in the CSA group and –0.095 in the Pred/AZA group. Neither slope was statistically different from zero. These data suggest that allograft function is not significantly depressed by CSA at 48 months post transplantation and that there is no greater rate of decline in allograft function up to 70 months post transplantation in patients receiving CSA when compared with the AZA/Pred group.     

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.     

Pharmacokinetics and pharmacodynamics in renal transplant recipients under treatment with cyclosporine and Myfortic

INTRODUCTION: Efficacious prophylaxis of acute rejection episodes (ARE) requires adequate exposure to each component of the immunosuppressive treatment from the first days after renal transplantation. The aim of the present study was to evaluate the correlation between cyclosporine (CsA) and mycophenolic acid (MPA) exposure based upon pharmacokinetics (PK) and pharmacodynamics (PD) and 6-month biopsy-proven acute rejection (BPAR) episodes and chronic allograft nephropathy on 6 month protocol biopsies. PATIENTS AND METHODS: We examined twenty-two first or second de novo renal transplant recipients treated with steroids, Sandimmune Neoral (CsA) and Myfortic (720 mg twice a day). PK (C0, C2, and AUC(0-12h)) for both drugs were determined on days 7, 90, and 180. Calcineurin activity, interleukin-2 and interferon-gamma synthesis as well as %CEM were tested at days 7 and 180. CsA dosages were adjusted by C2 monitoring. Collected data included: BPAR during the first 6 months and Banff histological parameters on the 6-month protocol biopsies. RESULTS: Eighteen of 22 patients completed 1 year follow-up under treatment. The 6-month BPAR was 18% (4/22). Six-month protocol biopsies in 50% of 14 recipients showed chronic allograft nephropathy 1. At day 7, CsA C2 and AUC median values were 138 ng/mL and 6377 ng x h/mL, while C0 MPA was 1.0 microg/mL and AUC = 23.9 microg x h/mL. CsA C2 medians at 3 and 6 months were 1468 and 1720 ng/mL. MPA-AUC reached therapeutic targets at 3 months (32.3 microg x h/mL) and was 48.3 microg x h/mL at 6 months. Patients with BPAR showed lower CsA AUC (P = .06) and a significantly lower baseline inhibition of calcineurin activity (P < .005) than patients with no BPAR. An increase in mesangial matrix in 6-month protocol biopsies correlated with higher CsA C2 (P = .01). All biomarkers evaluated were significantly inhibited compared with the standard population. CONCLUSIONS: When Myfortic is administered together with CsA, it is advisable to begin with higher doses (720 mg x 3 days) to reach adequate PK targets and improve BPAR rates. To prevent chronic allograft nephropathy, lower CsA C2 should be targeted from 3 months.     

Long-term, low-dose cyclosporine treatment of renal allograft recipients. A randomized trial

Ninety-two adult renal allograft recipients, receiving baseline immunosuppression with CsA and prednisone, were assigned randomly to one of the following regimens. CsA was discontinued (D/C group) in 47 recipients who were then maintained on Aza and prednisone; or Aza was added to continued low-dose CsA and prednisone (triple drug [TD] group) in 45 patients. Entry into the study required an absence of rejection and a stable creatinine for at least four months prior to randomization. The mean month of randomization was 8.34 +/- 2.9 for the D/C group, and 7.2 +/- 3.2 for the TD group. Following randomization, a significantly greater rate of rejection (P less than .01) was observed in the D/C group (40%) than in the TD group (13%). With a mean follow-up of 30 months, 41/47 of D/C allografts (87.2%) and 39/45 TD allografts (86.6%) were functioning. Nevertheless, rejection had a persistent adverse effect on allograft function, in both the D/C and TD groups, up to 36 months following randomization. Parameters such as donor-type and rejection prior to randomization did not identify recipients at risk for rejection following randomization. Therefore, although the CsA withdrawal regimen might be ideal, the opportunity to select appropriate candidates remained elusive. In contrast, the safety of the TD regimen became apparent. Neither significant nephrotoxicity nor hypertension was observed, and the opportunity for less daily prednisone was evident. Despite its additional cost, the TD regimen utilizing indefinite low-dose CsA, is preferred.