A limited sampling strategy for cyclosporine area under the curve monitoring in lung transplant recipients.

We developed a limited sampling strategy (LSS) for predicting cyclosporine (Neoral) area under the curve from concentration-time data obtained specifically from lung transplant recipients. The optimal and most clinically convenient LSS for lung transplant recipients, based on patient wait time, number of blood samples required, percent prediction error, and assessment of predictive performance is one that requires 2 blood samples collected at 1 and 3 hours post-dose: AUC = 1.75 x C(1) + 4.91 x C(3) + 185.62.     

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.     

A limited sampling strategy for the estimation of 12-hour cyclosporine neoral area under the curve in Chinese cardiac transplant recipients

INTRODUCTION: This study determined the accuracy of a limited sampling strategy to predict the 12-hour cyclosporine neoral (CsA) area-under-the-curve (AUC) to provide a practical method for more accurate therapeutic drug monitoring (TDM) of CsA in Chinese heart transplant recipients. METHODS: Blood samples were collected at 0 (before the dose), and 0.5, 1, 2, 3, 4, 6, 8, 10, as well as 12 hours after CsA oral administration in 13 de novo heart recipients receiving oral CsA bid after rabbit antithymoglobulin sequential immuno-induction. Pharmacokinetics were analyzed for the first dose (PK-1) and the steady state dose (PK-2, 1 month after transplantation). The limited sampling strategies included single-point, 2-point, and 3-point prediction of AUC using multiple linear regression analyses. RESULTS: Comparing the AUC/mg dose, PK-1 was much lower than PK-2 (25.2 +/- 11.4 ng x h/mg x mL vs 45.4 +/- 12.9 ng x h/mg x mL; P = .0005 using paired t test). The correlations of each single-point blood level of PK-1 with the AUC were lower than those of the corresponding sampling time in PK-2. In the PK-2 study, C4 had the best correlation (r2 = 0.732; P = .00) as a single-point to predict AUC, but the 2-point C2 + C12 had a higher correlation (r2 = 0.937; P = .00). Among the 3-point combinations, C2 + C4 + C12 showen the best prediction (r2 = 0.982; P = .00) of the AUC in PK-2. CONCLUSION: The bioavailability of CsA was lower in PK-1 than in PK-2. At steady state, we recommend C2 + C12 to predict AUC because it is accurate and not labor-intensive.     

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     

Neoral monitoring by limited sampling area under the concentration time curve in stable indian renal transplant recipients

The optimization of cyclosporine (CsA) immunosuppression remains a challenge because of the narrow therapeutic window and highly variable pharmacokinetics (PK). The highly variable PK were improved by the introduction of the current microemulsion preparation Neoral. However, the best clinical benefit of this CsA microemulsion can only be obtained by regular PK monitoring. During the past decade, various PK strategies have been proposed, such as C(0), C(2), level monitoring, abbreviated or limited sampling approach, and various prediction algorithms to replace the conventional area under the curve (AUC). In this study we evaluated the Neoral PK in stable Indian renal transplant recipients using a limited sampling approach. The C(0) (mean +/- SE) was 175 +/- 15 ng. mL(-1); C(max) 970 +/- 101 ng. mL(-1), and the AUC (0-4) 2734 +/- 258 ng. h. mL(-1). The C(0) showed a poor relationship to AUC (0-4) (r =.65) but high correlations were obtained with C(2) (r = 0.93) and C(3) (r =.96). Our finding suggest that stable Indian renal transplant recipients should either be monitored using C(2) or C(3).     

Compliance with cyclosporine in adolescent renal transplant recipients

  Inadequate compliance with prescribed medication regimens in children is complex and poorly understood. We measured the extent and pattern of noncompliance with cyclosporine in our adolescent renal transplant population and attempted to determine factors associated with poor compliance. After informed consent, each patient was provided cyclosporine capsules in a medication bottle equipped with an electronic monitoring device (MEMS-4) in the lid. Of the 24 patients eligible, 19 patients (8 female, 11 male) completed the study. Four (21%) patients took less than 80% of the prescribed cyclosporine doses. Five (26%) patients took drug holidays involving ≥3 consecutive doses. There was a trend towards improved compliance with the evening dose (88.5% vs. 93.4%, P = 0.09) and a downward trend in compliance over the course of the study (P = 0.17). None of the variables tested were found to be associated with noncompliance. Experienced physicians and nurses were able to identify 2 of the 4 individuals who were identified by MEMS as noncompliant. Additionally, 2 of the 4 noncompliant patients demonstrated low cyclosporine trough levels (<50 ng/ml). Noncompliance with cyclosporine regimens occurs commonly in adolescent renal transplant recipients. Unexpectedly low cyclosporine levels are strongly suggestive of noncompliance, whereas other variables, including prediction by physicians and nurses intimately involved in the care, were not reflective of noncompliance. Received October 19, 1996; received in revised form February 18, 1997; accepted March 18, 1997     

Long-term assessment of renal function under cyclosporine in pediatric heart transplant recipients.

Renal function was monitored in eight children who were long-term survivors of heart transplantation and who were treated with cyclosporine. Both creatinine clearance and true glomerular filtration rate remained normal 17 to 69 months after transplantation. The survival rate was 80% at 6, 12, and 24 months, and the rejection rate in survivors was only 0.37. Thus adequacy of renal function can be preserved, without jeopardizing overall transplant results, by using small doses of cyclosporine.     

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.     

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.     

Endothelial dysfunction in renal transplant recipients maintained on cyclosporine

BACKGROUND: Hypertension is almost universal following renal transplantation and may contribute to the already poor cardiovascular prognosis of this group. Cyclosporine-induced hypertension is a particular problem and has variously been attributed to increased sympathetic nerve activity, salt and water retention, and increased circulating endothelin levels. However, the effects of cyclosporine on the L-arginine/nitric oxide (NO) system in vivo in humans are unknown. In this present study, we examined basal and stimulated NO production from the vascular endothelium in cyclosporine-treated renal transplant recipients using the technique of forearm venous plethysmography. METHODS: In study 1, stimulated NO production was assessed in 9 cyclosporine-treated renal transplant recipients (CsA), 7 azathioprine-treated renal transplant recipients (AZA), and 12 controls, using carbachol (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). In study 2, basal NO production was assessed in 9 cyclosporine-treated patients and 11 controls using L-NMMA (inhibits NO synthase), with norepinephrine as a control vasoconstrictor. Drugs were infused into the nondominant forearm through a sterile 27-gauge needle, and changes in forearm blood flow (FBF) were measured using venous occlusion plethysmography. RESULTS: In study 1, sodium nitroprusside caused a similar dose-dependent increase in FBF in all groups. However, the median (range) percentage increase FBF to carbachol (3 micrograms/min) was markedly reduced in the CsA patients (188.8; 72.5 to 385.1) compared with AZA patients (378.1; 124.0 to 548.9; P = 0.042) and to controls (303.8; 124.8 to 813.3; P = 0.028). In study 2, the maximum percentage reduction in FBF to L-NMMA (4 mumol/min) was less pronounced in CsA patients (-19.5; -4.7 to -63.1) compared with controls (-39.5; -15.7 to -52.8; P = 0.056), and while controls vasoconstricted to the maximum dose of norepinephrine (240 pmol/min) as expected (-26.9; -1.4 to -38.6), CsA patients as a group tended to vasodilate (7.9; -36.8 to 92.6; P = 0.02). CONCLUSION: These data demonstrate impaired stimulated and basal NO production in CsA patients, indicating endothelial dysfunction. This may predispose patients to atherosclerosis and may be involved in the etiology of post-transplant hypertension.     

Epithelial-to-mesenchymal transition predicts cyclosporine nephrotoxicity in renal transplant recipients

Maintenance immunosuppression with cyclosporine A (CsA) can cause nephrotoxicity in renal transplant recipients. Identifying patients at increased risk for CsA nephrotoxicity may allow interventions to prolong graft survival. Here, we studied the effect of early CsA withdrawal or maintenance among 96 kidney recipients at risk for interstitial fibrosis and tubular atrophy (IF/TA) on the basis of tubular expression of vimentin and β-catenin in a protocol biopsy performed 3 months after transplant. In this retrospective analysis of biopsies collected during a randomized trial of early withdrawal of CsA or mycophenolate mofetil, the semiquantitative score of early phenotypic changes suggestive of epithelial-to-mesenchymal transition (EMT) progressed with time among those maintained on a CsA-containing regimen. EMT-positive grafts displayed a significantly higher IF/TA score and greater progression of the IF/TA score at 12 months (P=0.001 and 0.008, respectively). EMT-positive grafts exposed to CsA also had a greater decrease in estimated GFR compared with EMT-negative grafts exposed to CsA and EMT-positive grafts withdrawn from CsA exposure. Multivariable analysis revealed that the presence of EMT was an independent risk factor for a 10% decline in graft function up to 4 years posttransplant (odds ratio 4.49; 95% confidence interval 1.02 to 19.9). Collectively, these data demonstrate that changes consistent with EMT are strong prognostic biomarkers in renal transplant recipients exposed to CsA.