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.     

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.     

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.     

Long-term effects of cyclosporine on renal function in liver transplant recipients

The long-term effects of cyclosporine on renal function were evaluated in eleven liver transplant recipients over a 6-26-month follow-up period. Renal hemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF]) fell 60% postoperatively, subsequently improved, and stabilized at 45-60% of normal despite continued drug administration. Tubular sodium transport studies during water diuresis suggested that the proximal tubule is a major site of cyclosporine nephrotoxicity. In contrast to the acute effects of cyclosporine on renal function, the fraction of glomerular filtrate reabsorbed in the proximal tubule was less in the patient group while the fractional excretion of sodium, potassium, and phosphate was increased. When the fraction of filtered sodium reabsorbed in the diluting segment was examined as a function of sodium delivery, functional impairment occurred in the diluting segment as well. Eight renal biopsies performed in six patients 4-29 months posttransplantation showed only mild to moderate changes, predominantly vascular, which correlated poorly with corresponding renal function. These data showed that long-term cyclosporine administration produced early and persistent depression of both hemodynamic and tubular function. A functional rather than structural mechanism appears to be more significant during this period of observation.     

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.     

Limited utility of cyclosporine C2 monitoring in heart transplant recipients receiving ketoconazole

The aim of the study was to compare 2 hours postdose concentration (C2) of CyA in stable patients receiving ketoconazole concomitantly late after heart transplantation (OHT) with patients not receiving ketoconazole. Routine C2 and C1 (1 hour postdose concentration) of CyA monitoring (FPIA, AxSYM, Abbott) along with C0 (trough level) were performed in 64 elective patients. The KETO group consisted of 29 patients receiving 200 mg of ketoconazole daily along with CyA; the remaining 35 patients were included into the control group. Patient characteristics (KETO vs control group) were as follows: age, 49 +/- 11 versus 48 +/- 12 years; percentage of male patients, 93 versus 80; follow-up post-OHT, 4.3 +/- 2 versus 5.3 +/- 2 years. Target C0 of CyA was 175 to 225 ng/mL; CyA doses remained stable for at least 1 month. We compared maintenance doses of CyA, C0, C1, C2 of CyA, number of biopsy-proven acute cellular rejection (AR) during the one year and after the first year post-OHT, and creatinine in both groups. Statistical significance was assessed using Mann-Whitney U test. Results were as follows (KETO versus control group): CyA dose, 53 +/- 30 versus 216 +/- 69 mg, P <.000001; C0, 181 +/- 77 versus 160 +/- 53 ng/mL, NS; C1, 406 +/- 78 versus 803 +/- 317 ng/mL, P =.000001); C2, 397 +/- 174 versus 689 +/- 284 ng/mL, P =.000001, AR during the first year after OHT, 2.8 +/- 1.9 versus 2.3 +/- 1.6, NS; AR beyond first year after OHT, 0.2 +/- 0.5 versus 0.7 +/- 0.9, P =.03); creatinine, 181 +/- 50 versus 160 +/- 114 micromol/L NS. In conclusion; C2 monitoring in stable heart transplant recipients receiving cyclosporine and ketoconazole concomitantly late after procedure does not seem to be sufficient to estimate the immunosuppressive effect of this combination.     

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.     

Sulfinpyrazone reduces cyclosporine levels: a new drug interaction in heart transplant recipients

BACKGROUND: Management of cyclosporine (CsA)-associated hyperuricemia in heart transplantation (HT) is difficult. Because of the myelotoxicity of combined allopurinol and azathioprine, we tested sulfinpyrazone. METHODS: We studied 120 HT recipients (109 men; mean age at HT, 52+/-10 years). All had received allopurinol for at least 6 months, which was stopped for 1 month before initiation of sulfinpyrazone. Mean follow-up from HT to onset of sulfinpyrazone (200 mg/day) was 59+/-41 months. We stopped the drug after 6+/-2 months. We compared CsA level and daily dose, serum creatinine, blood urea, and uric acid at onset and before interruption of sulfinpyrazone and, as control, in the last 6 months of allopurinol. RESULTS: Mean uricemia decreased with allopurinol (0.58+/-0.12 vs. 0.41+/-0.07 mmol/liter, p = 0.0001) as well as with sulfinpyrazone (0.51+/-0.13 vs. 0.40+/-0.12 mmol/liter, p = 0.0001). Mean creatinine increased (171+/-42 and 164+/-35 micromol/liter, p = 0.01) with allopurinol, whereas it tended to decrease with sulfinpyrazone (160+/-35 and 154+/-48 micromol/liter, p = NS). Mean urea did not change with allopurinol (14+/-5 vs. 15+/-7 mmol/liter, p = NS), but fell with sulfinpyrazone (14.01+/-5 vs. 12.60 +/-5 mmol/liter, p = 0.0004). Mean CsA levels were constant with allopurinol (193+/-73 vs. 188+/-65 ng/ml, p = NS), although CsA dose was slightly reduced (2.7+/-0.8 vs. 2.6+/-0.8 mg/kg/day, p = 0.007). Conversely, CsA levels dropped with sulfinpyrazone (183+/-89 vs. 121 +/-63 ng/ml, p = 0.0001) despite an increase in CsA daily dose (2.6 +/-0.9 vs. 2.8+/-0.9 mg/kg/day, p = 0.0001). Two subjects were treated for acute rejection. We observed no other side effects. In HT recipients sulfinpyrazone, as an alternative to allopurinol, is effective in achieving metabolic control of hyperuricemia. However, this drug reduced CsA levels, thus the risk of rejection is present.     

Early infections in kidney, heart, and liver transplant recipients on cyclosporine

Eighty-one renal, seventeen heart, and twenty-four liver transplant patients were followed for infection. Seventeen renal patients received azathioprine (Aza) and prednisone as part of a randomized trial of immunosuppression with 21 cyclosporine-and-prednisone-treated renal transplant patients. All others received cyclosporine and prednisone. The randomized Aza patients had more overall infections (P less than 0.05) and more nonviral infections (P less than 0.02) than the randomized cyclosporine patients. Heart and liver patients had more infections than cyclosporine renal patients but fewer infections than the Aza renal patients. There were no infectious deaths in renal transplant patients on cyclosporine or Aza, but infection played a major role in 3 out of 6 cardiac transplant deaths and in 8 out of 9 liver transplant deaths. Renal patients on cyclosporine had the fewest bacteremias. Analysis of site of infection showed a preponderance of abdominal infections in liver patients, intrathoracic infections in heart patients, and urinary tract infections in renal patients. Pulmonary infections were less common in cyclosporine-treated renal patients than in Aza-treated patients (P less than 0.05). Aza patients had significantly more staphylococcal infections than all other transplant groups (P less than 0.005), and systemic fungal infections occurred only in the liver transplant group. Cytomegalovirus (CMV) shedding or serological rises in antibody titer, or both occurred in 78% of cyclosporine patients and 76% of Aza patients. Of the cyclosporine patients, 15% had symptoms related to CMV infection. Serological evidence for Epstein Barr Virus infection was found in 20% of 65 cyclosporine patients studied. Three had associated symptoms, and one developed a lymphoma.     

Cardiovascular risk profile after conversion from cyclosporine A to tacrolimus in stable renal transplant recipients

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in renal recipients. In addition to steroids, cyclosporine A (CsA) has been implicated in contributing to increased cardiovascular risk. Conversion from CsA to tacrolimus (TAC) has been shown to improve hyperlipidemia and hypertension, but little is known about the differential effects of CsA versus TAC on other cardiovascular risk factors. We investigated overall cardiovascular risk profile after conversion from CsA to TAC. METHODS: This was an open-label, single-arm prospective study; 22 adult renal recipients who were receiving CsA-based immunosuppression with serum total cholesterol greater than 200 mg/dL more than 1 year after transplantation were enrolled. CsA was replaced by TAC. Blood pressure, fasting lipid profile, homocysteine, fibrinogen, C-reactive protein, hemoglobin A1c, and creatinine were measured at baseline and at 3 and 6 months after conversion. RESULTS: There was a significant improvement in fibrinogen (366 +/- 81 - 316 +/- 65 mg/dL, P <0.001), total cholesterol (250 +/- 50 - 207 +/- 29 mg/dL, P <0.001), and low-density lipoprotein cholesterol (155 +/- 43 - 121 +/- 24 mg/dL, P <0.001) after conversion. No new onset or worsening of diabetes mellitus was observed after conversion. There were no significant differences in HDL cholesterol, triglycerides, homocysteine, C-reactive protein, hemoglobin A1c levels, serum creatinine, mean blood pressure, and mean number of antihypertensive medications required before and after conversion. CONCLUSIONS: Our results indicate that conversion to low-dose TAC may be preferable over CsA for chronic maintenance immunosuppression because it improves the overall cardiovascular risk profile without any apparent adverse effects.     

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.     

Treatment of tacrolimus-related adverse effects by conversion to cyclosporine in liver transplant recipients

When tacrolimus side effects persist despite dose reduction, conversion to cyclosporine-based immunosuppression (CyA) is necessary. We characterized tacrolimus side effects that warranted discontinuation of the drug, and outcomes after conversion. Of 388 liver recipients who received tacrolimus as primary immunosuppression, 70 required conversion to CyA. We recorded indication for conversion, whether conversion was early or late after transplantation, tacrolimus dose and trough blood level at conversion, and incidence of rejection after conversion. Conversion was early in 29 patients (41.4 %) and late in 41 (58.6 %). Indications for early conversion were neurotoxicity (20), (insulin-dependent) diabetes mellitus (IDDM) (5), nephrotoxicity (3), gastrointestinal (GI) toxicity (6), and cardiomyopathy (1), and for late conversion were neurotoxicity (15), IDDM (12), nephrotoxicity (3), GI toxicity (5), hepatotoxicity (6), post-transplant lmphoproliferate disease (PTLD) (2), cardiomyopathy (1), hemolytic anemia (1), and pruritis (1). All early-conversion patients showed improvement/resolution of symptoms. Among late-conversion patients, 37 (90.2 %) had improvement/resolution; in 4 (9.8 %), adverse effects persisted. The overall rejection rate was 30 %. Sixty-two patients (88.6 %) are alive with functioning grafts 686 ± 362 days (range, 154–1433 days) after conversion. When tacrolimus side effects are unresponsive to dose reduction, conversion to CyA can be accomplished safely, with no increased risk of rejection and excellent long-term outcome. Received: 26 February 1999/Revised: 5 November 1999/Accepted: 9 November 1999     

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