Everolimus and reduced cyclosporine trough levels in maintenance heart transplant recipients

BACKGROUND: Long-term survival of patients after oHTX significantly increased over the last years, but CAV and chronic renal failure due to nephrotoxic side-effects of CNIs still remain unsolved problems. Everolimus has shown to reduce acute cellular rejection and may allow CsA dosage reduction. In this study the effectiveness of Everolimus in combination with CsA dosage reduction in maintenance oHTX immunosuppression and the influence on renal function was tested. METHODS: 37 patients (30 male, 7 female) after oHTX were divided into group A (n = 20) receiving Everolimus in combination with CsA and prednisolone and group B (n = 17) under standard immunosuppression with CsA, MMF and prednisolone. Patients received 1.0 mg to 1.5 mg Everolimus per day and target Everolimus trough levels were between 3 and 8 ng/ml. Death, safety, side effects, BPAR, trough levels, and routine laboratory values especially creatinine levels were monitored over a follow-up period of 8 months retrospectively and statistically evaluated. RESULTS: A significant reduction of CsA dosage (p < 0.001) and a significant CsA trough level reduction (p < 0.001) to a median CsA trough level of 68.5 ng/ml were achieved in group A. Mean Everolimus trough levels were reached within 1 week and 2 months. Renal function was stable in both groups. No statistical differences in BPAR, hospitalization rates or triglyceride levels were observed. Cholesterol levels significantly increased in group B (p = 0.024). CONCLUSION: CsA trough levels and dosage can be significantly reduced in combination with Everolimus without higher rejection rates and with stable kidney function in oHTX patients.     

Increased morbidity and high variability of cyclosporine levels in pediatric heart transplant recipients.

OBJECTIVES: This study analyzed the relationship of variability in routine trough cyclosporine (CSA) levels to morbidity after pediatric cardiac transplantation. BACKGROUND: Due to high interindividual variation between dosage and blood concentrations, trough surveillance CSA levels are routinely performed after cardiac transplantation to adjust dosages. In addition, trough CSA levels have been used as a measure of patient compliance in transplant recipients. Recent investigations have demonstrated a relationship between late rejection and mistimed CSA dosing intervals, which could also lead to CSA levels that are incorrectly presumed to be trough levels. METHODS: Trough surveillance whole-blood CSA levels were retrospectively reviewed in 49 pediatric heart transplant recipients who had a median follow-up of 42 months (range 6 to 138 months). All patients received the same immunosuppression regimen (CSA, azathioprine, and steroids), the same CSA-level surveillance protocol, and the same stabilization of CSA dose and level in the therapeutic range (150 to 300 ng/ml) prior to hospital discharge. CSA levels drawn because of coexisting phenomena (drug interaction, gastroenteritis) that could cause CSA-level fluctuation were excluded from analysis. Cyclosporine variability was measured as the percentage of CSA levels that were considered sub-therapeutic (< or = 100 ng/ml), toxic (> or = 450 ng/ml), or both. Cyclosporine-level variability was then analyzed in respect to demographic and outcome variables. RESULTS: For the group, the median percentage of sub-therapeutic levels was 3% (range, 0% to 16%); the median percentage of toxic levels was 5% (range, 0% to 36%); the median of the combination of sub-therapeutic and toxic levels was 10% (0% to 38%). Eight of the 49 patients (16%) has a high (>20%) percentage of sub-therapeutic + toxic levels or high CSA variability. High CSA variability was significantly associated with recipients > 12 months of age (p = 0.028), and recipients with a history of non-compliance (p < 0.001). Patients with high CSA variability had a significantly higher median number of hospitalized days per year of follow-up (p = 0.036), higher rate of recurrent rejection (> or = 2 episodes; p = 0.0003), and higher death rate more than 6 months after transplant (p = 0.01). CONCLUSIONS: Although this study could not determine cause, high variability in trough CSA levels was a marker for pediatric heart transplant recipients at greater risk for recurrent rejection and hospitalization after transplantation.     

Therapeutic drug monitoring of tacrolimus in cardiac transplant recipients: a comparison with cyclosporine neoral

This study compares the pharmacokinetics of tacrolimus (TAC) and cyclosporine Neoral (CsA) in cardiac transplant recipients. METHODS: Twenty-six de novo cardiac recipients were prospectively and randomly assigned to receive oral TAC- or CsA-based regimens after 5 to 6 days of rabbit antithymocyte globulin induction. 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 drug administration. The pharmacokinetics of the first dose (PK-1) and at steady state (PK-S, 1 month after transplantation) were analyzed. RESULTS: Comparing the AUC per milligram dose, there was no significant difference between PK-1 and PK-S among TAC (46.0 +/- 24.3 ng x h/mg x mL versus 69.0 +/- 43.9 ng x h/mg x mL, P = .15 by paired t-test), but a significant difference in CsA (25.2 +/- 11.4 ng x h/mg x mL versus 45.4 +/- 12.9 ng x h/mg x mL, P = .0005 by paired t-test). This means better TAC absorption in the early post-heart transplant period. Using a single-point blood level to predict AUC, TAC showed a significantly higher correlation than CsA at all corresponding sampling times. Besides, C12 in both PK-1 and PK-S of TAC displayed good correlations to the AUC (r2 = .895, P = .00 in PK-1 and r2 = .81, P = .00 in PK-S). The TAC trough level was accurate enough to predict the AUC. CONCLUSION: The pharmacokinetic profile of TAC is more reliable than that of CsA in the early post-heart transplant period. A high correlation of trough blood levels with AUC omits the requirement for a multiple sampling strategy to more accurately measure AUC as is needed with CsA.     

Beneficial pharmacokinetic interaction between cyclosporine and itraconazole in renal transplant recipients

BACKGROUND: Itraconazole is often given for fungal prophylaxis to renal transplant recipients, who require concomitant cyclosporine in the immediate posttransplant period. We determined the extent of the pharmacokinetic interaction between cyclosporine and itraconazole oral solution in renal transplant recipients and the effect on daily drug costs. METHOD: This was a single-center, open-label, nonrandomized study. Posttransplantation, renal transplant recipients received itraconazole solution 200 mg twice daily and cyclosporine, dosed to achieve target concentrations. Once at steady state, blood samples were collected over 12 hours for pharmacokinetic evaluation of cyclosporine, itraconazole, and hydroxy-itraconazole. Itraconazole was discontinued after approximately a 3-month prophylaxis regimen. Cyclosporine doses were titrated to achieve target concentrations and cyclosporine concentrations were once again determined when steady state was achieved. A noncompartmental analysis was used to analyze cyclosporine pharmacokinetic parameters. The pharmacoeconomic impact was measured based on the percent change in dose of cyclosporine when administered with and without itraconazole. Drug costs were calculated using the average wholesale price. The cost per patient, as well as the average cost, was calculated for the cyclosporine/itraconazole combination, as well as the cyclosporine regimen alone. RESULTS: Eight renal transplant recipients completed the study. All were included for itraconazole analyses and seven for cyclosporine analyses. Mean peak and trough itraconazole levels were 1.64 +/- 0.82 and 1.23 +/- 0.90 microg/mL respectively. Mean peak and trough hydroxy-itraconazole levels were 2.37 +/- 1.55 and 2.20 +/- 1.48 microg/mL, respectively. While on itraconazole, a 48% reduction in the mean total daily dose of cyclosporine was necessary to maintain target concentrations (171 +/- 63.6 versus 329 +/- 103.5 mg, P =.003). This reduction in cyclosporine dose resulted in a discounted itraconazole daily drug cost of approximately 29.5%. CONCLUSION: Administering itraconazole with cyclosporine allows for a decrease in the cyclosporine dose, thus lowering daily drug costs and providing adequate antifungal coverage with itraconazole and hydroxy-itraconazole trough concentrations above the MIC(90) of Candida and Aspergillus spp.     

Noncardiac surgery in heart transplant recipients in the cyclosporine era.

As survival and quality of life continue to improve for cardiac transplant recipients, there is an ever-increasing possibility that these patients will present for elective and/or emergency surgery outside of a transplantation center. Cyclosporine therapy has been a major factor in extending homograft survival, but recent studies have suggested that cyclosporine administration increases the duration of action of some anesthetics. The authors evaluated the influence on anesthetic management of cardiac transplantation and chronic cyclosporine therapy in a retrospective review of all postcardiac transplant patients who presented for noncardiac surgery at the study institution. The data suggest that a number of commonly used anesthetic techniques can be administered safely to these patients when no evidence of graft rejection is present. No clinically significant prolongation of anesthetic effect was encountered following the doses of anesthetics described.     

Proton pump inhibitor co-medication reduces active drug exposure in heart transplant recipients receiving mycophenolate mofetil

Background

Proton pump inhibitors (PPIs) are often prescribed for gastrointestinal discomfort after heart transplantation. This study investigated the impact of PPI use on mycophenolic acid (MPA) pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) in combination with a calcineurin inhibitor (tacrolimus [TAC]/cyclosporine [CsA]) or mammalian target of rapamycin inhibitor (sirolimus/everolimus).

Methods

Abbreviated MPA areas under the curve (AUCs; 0, 30, and 120 minutes after morning intake) were obtained in 19 patients on a PPI (initial examination) and 1 month after PPI discontinuation (follow-up). Mean patient age was 58.2 ± 8.8 years, and mean time after transplantation was 2.3 ± 4.0 years (range, 0.2–13.0 years).

Results

At initial examination mean daily MMF dose was 2.2 ± 0.8 g. MMF dose was kept unchanged for the duration of study (P = ns). Mean predose (C0) MPA serum concentrations were insignificantly lower with PPI comedication (2.5 ± 2.2 mg/L vs 2.8 ± 1.7 mg/L; P = .15). Dose-adjusted abbreviated MPA AUCs (adjusted to morning dose) were significantly lower during PPI therapy (45.2 ± 20.3 vs 65.2 ± 38.8 mg · h/L · g [MMF]; P = .02).

Conclusions

Patients with PPI comedication during MMF therapy show significantly lower exposure to mycophenolic acid determined by dose-adjusted abbreviated MPA AUCs. Although the clinical relevance of this pharmacokinetic interaction was not determined in this study, MPA drug monitoring by limited sampling strategies might be helpful during changes in antacid comedication in patients on MMF.     

Pharmacokinetics of cyclosporine in heart transplant recipients receiving metabolic inhibitors.

BACKGROUND: Inhibitors of cyclosporine metabolism are commonly co-administered with cyclosporine in transplant recipients. The aim of this study was to compare cyclosporine pharmacokinetics using the conventional formulation (Sandimmune) and after switching to the microemulsion (Neoral) formulation, in stable heart transplant recipients receiving various cyclosporine metabolic inhibitors. METHODS: Steady-state blood concentration-time profiles of Sandimmune were studied in 47 transplant recipients receiving either cyclosporine alone (Group A, n = 11) or in combination with diltiazem (120 mg/day, Group B, n = 11), ketoconazole (200 mg/day, Group C, n = 13), or both ketoconazole and diltiazem (200 and 120 mg/day, respectively, Group D, n = 12), and restudied 1 week after switching to Neoral. RESULTS: Neoral resulted in more rapid cyclosporine absorption as judged by the shorter absorption half-lives in all groups (p < 0.05). The mean percentage increase in the values of area-under-the-concentration-time curve was 42% and 37.5% higher for Neoral compared with Sandimmune for Groups A and B, respectively, but only 5.4% higher for Group C and 9.5% higher for Group D. The mean morning trough concentration of cyclosporine was not significantly different after administration of Neoral compared with Sandimmune in any of the groups studied (179 vs. 167 microg/liter for Group A; 171 vs. 147 microg/liter for Group B; 189 vs. 194 microg/liter for Group C; and 181 vs 201 microg/liter for Group D). Neoral did not alter serum concentrations of sodium, potassium, creatinine, and urea in any of the study groups. CONCLUSIONS: The faster absorption and improved bioavailability of cyclosporine (around 40%) with Neoral compared with Sandimmune was not seen in patients receiving ketoconazole, where in fact cyclosporine bioavailability was already maximal. Mean morning trough levels of cyclosporine did not reflect the improvement in bioavailability seen in patients switching from Sandimmune to Neoral. Cyclosporine dose adjustment may be needed when switching from Sandimmune to Neoral for patients not receiving sparing agents or who receive diltiazem, but trough levels cannot necessarily be relied upon to determine the degree of adjustment needed. For patientson ketoconazole, the absorption profile is already optimized and no dosage alteration seems necessary.     

Monitoring of cyclosporine levels in transplant recipients using self-administered fingerprick sampling

Use of C(2) monitoring for cyclosporine A (CsA) microemulsion results in improved clinical outcomes vs. trough (C(0)) monitoring. Logistical issues include accurate timing of the C(2) sample; requirement for sample dilution with most standard assay techniques; and inconvenience for patients. Recently, it has been shown that CsA concentrations in capillary blood correlate closely with levels in venepuncture samples, and that liquid chromatography tandem mass spectrometry (LC-MS/MS) can analyse CsA concentration using undiluted capillary blood from fingerprick samples. In a study to assess the feasibility of CsA monitoring, 52 stable heart transplant patients were provided with kits to take fingerprick trough and C(2) blood samples at home, returning them to the laboratory by post for LC-MS/MS analysis. In total, 225 samples were provided, of which 14 (6%) were unsuitable for analysis because of clotting (n = 10) or insufficient volume (n = 4). Discomfort was not a problem and initial difficulties that some patients reported in taking the samples resolved with experience. All samples were returned by the postal system in a timely manner. Use of fingerprick assays could allow transplant physicians to have access to C(2) levels when patients visit the clinic for review, and avoids the need for patients to attend the clinic or local healthcare centre solely for venepuncture. A barrier to more widespread introduction of fingerprick testing is likely to be lack of suitable MS facilities and trained personnel. In conclusion, self-administered fingerprick testing for CsA blood levels is practical to implement and highly convenient for patients and offers advantages for the transplant team.     

Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients

BACKGROUND: Triple drug treatment consisting of mycophenolate mofetil (MMF), in a standard dose of 2 g daily, combined with cyclosporine (CsA) and prednisone, has become the standard immunosuppressive regimen after kidney transplantation in many centers. The need for therapeutic drug monitoring of mycophenolic acid (MPA) has not yet been established. Several drug interactions with MMF are known. We investigated the influence of CsA withdrawal on MPA trough levels in renal transplant patients. METHODS: Fifty-two patients were treated with 1 g of MMF twice daily, and prednisone and CsA targeted between 125 and 175 ng/ml for 6 months after transplantation. At 6 months after transplantation, 19 patients were randomized for continuation of triple therapy (group A), 19 patients discontinued CsA (group B), and 14 patients discontinued prednisone (group C). We compared 12-hr fasted MPA trough levels at 6 and 9 months after transplantation within and between these groups. RESULTS: MPA trough levels during treatment with CsA, MMF, and prednisone were significantly lower than those during treatment with MMF and prednisone only (group B); median levels were 1.87 mg/L (range: 0.56-5.27) vs. 3.16 mg/L (range: 0.32-7.78), respectively (P=0.002). MPA trough levels in groups A and C did not change between 6 and 9 months after transplantation; group A median levels were 1.87 (range: 0.31-4.32) vs. 1.53 mg/L (range: 0.36-3.70), and group C median levels were 1.62 (range: 0.69-10.34) vs. 1.79 mg/L (range: 0.54-6.00), respectively. At 9 months after transplantation, patients in whom CsA was discontinued had higher MPA trough levels as compared with patients who continued the use of triple therapy (P=0.001) or patients in whom steroids were withdrawn (P=0.014). CONCLUSION: A significant increase of MPA trough levels was found after discontinuation of CsA (6 months after transplantation), resulting in almost a doubling of MPA trough levels at 9 months after transplantation. This resulted in increased MPA levels in patients without CsA as compared to MPA levels in patients continuing triple therapy or discontinuing prednisone.     

Reduction of cyclosporine following the introduction of everolimus in maintenance heart transplant recipients: a pilot study

Data are scarce concerning the calcineurin inhibitor dose reduction required following introduction of everolimus in maintenance heart transplant recipients to maintain stable renal function. In a 48-week, multicenter, single-arm pilot study in heart transplant patients >12 months post-transplant, everolimus was started at 1.5 mg/day (subsequently adjusted to target C ₀ 5–10 ng/ml). Mycophenolate mofetil or azathioprine was discontinued on the same day and cyclosporine (CsA) dose was reduced by 25%, with a further 25% reduction each time calculated glomerular filtration rate (cGFR) decreased to <75% of baseline. Of 36 patients enrolled, 25 were receiving everolimus at week 48. From baseline to week 48, there was a mean decrease of 44.5%, 50.9% and 44.6% in CsA dose, C ₀ and C ₂, respectively. Mean cGFR was 68.9 ± 14.5 ml/min at baseline and 61.6 ± 11.5 ml/min at week 48 ( P  = 0.018). The prespecified criterion for stable renal function was met, i.e. a mean decrease ≤25% of cGFR from baseline. Two patients experienced biopsy-proven acute rejection Grade 3A (5.6%). Between baseline and week 48, there were significant increases in total cholesterol, LDL-cholesterol and triglycerides, and small but significant elevations in liver enzymes. This 1-year pilot study suggests that CsA dose reduction of ca. 40% after initiation of everolimus was associated with a decrease in cGFR, however, based on the prespecified criteria stable renal function was attained.     

Pathologic assessment of cardiomyocytes in heart transplant recipients treated with rapamycin or cyclosporine

The aim of this study was to compare cardiomyocytes and stromal pathology in heart transplant recipients treated with rapamycin (RAPA) versus cyclosporine (CyA). We analyzed elective biopsies obtained during first 3 months after heart transplantation in four patients treated with RAPA (24 biopsies) and seven patients receiving CyA (49 biopsies). Additional medications in both groups consisted of mycophenolate mofetil or azathioprine and prednisone. The intensity of rejection was assessed using the ISHLT scale; it was comparable in both groups based upon the number of results showing significant rejection and the average biopsy scores. Each slide was also examined under high-power magnification to sarcoplasmic and nuclear changes. Sarcoplasmic vacuolation, premyocytolysis and myocytolysis, nuclear staining, stromal fibrosis and edema, presence of vasculopathy, and lymphocytes infiltrating the myocardium occurred more frequently in the CyA group. The difference in the degree of hyperchromasia of the nuclei was highly significant (67% versus 10%, P <.00001). Our findings suggest that despite comparable levels of rejection as assessed using the ISHLT scale, patients treated with RAPA display fewer signs of cardiomyocytic alterations early after heart transplantation.