The clinical impact of 1:1 conversion from Neoral to a generic cyclosporine (Gengraf) in renal transplant recipients with stable graft function

The introduction of cyclosporine (CYA) to the immunosuppressive armamentarium has had a significant effect on graft survival. An improvement in the formulation from the oil-based to a microemulsion-based form has resulted in better absorption and more predictable CYA bioavailability. Since the introduction of the first microemulsion form (Neoral), several bioequivalent formulations are now available and are switched in a 1:1 fashion at pharmacies to curtail costs. The purpose of our study was to study the effect of a 1:1 switch from Neoral to Gengraf on CYA trough levels and serum creatinine (SRC) in renal transplant recipients with stable graft function. Eighty-two renal transplant recipients with stable graft function were enrolled in the study, and of these, 73 were switched to Gengraf, whereas nine remained on Neoral. The 13 patients switched to Gengraf required a dosage change after the mean CYA trough levels changed from 234 +/- 96 ng/mL at baseline to 289 +/- 102 ng/mL (p < 0.05) at 2 wk. With the adjustments in dosage, the levels approached the baseline trough concentrations (239 +/- 151 ng/dL). The nine patients who remained on Neoral had no change in the CYA levels or SCR. Nearly 20% of patients who switched to a bioequivalent CYA preparation required a dose adjustment to return to pre-conversion CYA trough levels. Our study raises serious concerns regarding the switchability of generic CYA for Neoral without careful follow-up therapeutic drug monitoring.     

Pharmacokinetics, efficacy, and safety of Iminoral compared with Neoral in healthy volunteers and renal transplant recipients

This study sought to evaluate the bioequivalence of Iminoral (test) versus Neoral (reference) in healthy volunteers, as well as safety and efficacy of Iminoral treatment in renal transplant recipients following conversion from Neoral. METHODS: After an overnight fast, 18 healthy volunteers received the assigned treatment (test or reference, 200 mg single dose) in a cross-over fashion with a washout period of 14 days. The blood samples were drawn at various times after drug administration. Cyclosporine blood concentration was measured by high-performance liquid chromatography using an ultraviolet detector. In the second phase of study, stable renal transplant patients who were on Neoral were enrolled in the study in an open-label manner. They were converted from Neoral to Iminoral based on a 1:1 dose equivalence. Cyclosporine trough levels and changes in serum creatinine, lipid profile, electrolytes, and uric acid were measured before and periodically after conversion for 6 months. RESULTS: The 90% confidence interval of the test/reference ratio was within the acceptable limits of 0.8 to 1.25. Relative bioavailability of Iminoral in healthy subjects was 99.0%. There was no significant difference in cyclosporine concentrations and serum creatinines following conversion to Iminoral in renal transplant patients (n=41). There were no reports of major toxicity or of graft rejection and no need for dose adjustment related to Iminoral. CONCLUSIONS: Single doses of Neoral and Iminoral are bioequivalent in healthy subjects. Renal transplant recipients maintained on Neoral can be safely and effectively converted to Iminoral on a 1:1 conversion ratio.     

Risk factors of cyclosporine nephrotoxicity after conversion from Sandimmune to Neoral

BACKGROUND: In 1995 - 1996, we switched from a once-daily Sandimmune dose to a twice-daily dose regimen of Neoral. Concurrent with the switch we changed our target trough level from 100 microg/l at 24 hours to the generally accepted 12-hour level of 150 microg/l. We performed a retrospective cohort study to assess cyclosporine toxicity following this switch and to identify risk factors for nephrotoxicity. PATIENTS AND METHODS: Of 212 patients with a stable graft function pre-conversion clinical parameters at 1 and 12 months post-conversion were compared with those at time of conversion. Cyclosporine nephrotoxicity was defined as a significant decline of the reciprocal of the serum creatinine concentration over time post-conversion in the absence of other obvious causes for declining graft function. Risk factors of cyclosporine nephrotoxicity were assessed using logistic regression analysis. RESULTS: The mean cyclosporine trough level rose from 87 microg/l at the time of conversion to 139 microg/l at 12 months post-conversion whereas the daily drug dose increased over the same period from 233 mg to 252 mg. Mean serum creatinine increased by 10% from 135 to 148 micromol/l (p < 0.001). Cyclosporine nephrotoxicity was present in 42 patients (20%). Cyclosporine dose and trough level did not predict nephrotoxicity but beta-blockers (OR 0.35, 95% CI 0.17-0.72) and calcium channel blockers (OR 0.35, 95% CI 0.19-0.82) reduced the risk of nephrotoxicity, independent from an effect on blood pressure. CONCLUSION: 20% of stable renal transplant patients experienced chronic cyclosporine nephrotoxicity after conversion from a once-daily Sandimmune regimen to a twice-daily Neoral regimen with dose adjustments to a trough level of 150 microg/l. beta-blockers and calcium channel blockers reduced the risk of nephrotoxicity.     

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.     

Improved absorption of cyclosporin A from a new microemulsion formulation: implications for dosage and monitoring

Recently, a new oral microemulsion formulation of cyclosporin A (CsA) — Neoral (Sandoz, Basle, Switzerland) — with a higher bioavailability has become available. Ten stable paediatric renal transplant recipients with excessive variations in CsA trough levels with the original Sandimmun (Sandoz, Basle, Switzerland) preparation were switched to Neoral on a 11 basis. Pharmacokinetic studies revealed impaired absorption of Sandimmun, in six patients. Compared with equal doses of Sandimmun, the 8-h area under the concentration-time curve increased from 1,422 to 2,657 ng×h/ml and the peak concentration rose from 319 to 824 ng/ml (P<0.01). In six patients with Sandimmun malabsorption, conversion on a 11 basis led to a reduction in creatinine clearance which was reversible after dose reduction by 9%–25%. With trough levels at the lower end of the present target range, creatinine clearance stabilised around pre-conversion values.     

CYCLOSPORIN A (CyA) MONITOrING BY CALCULATION OF AREA UNDER THE CURVE (AUC)

Background The introduction of CyA resulted in a significant prolongation in renal transplant survival but was complicated by the difficulty in distinguishing between transplant rejection and drug toxicity. More recently the conversion of stable transplant recipients to the microemulsion form of CyA resulted in significant nephrotoxicity at trough levels that were previously within the therapeutic range. We have studied AUC determinations as an alternative to trough monitoring for transplant recipients. Methods Fifty five renal transplant recipients underwent venesection prior to administration of their morning CyA dose (Pre) then 2 hours after the dose (post). The Pre (C0) and the post (C2) CyA levels were determined using the AXSYM system (Abbot) then the AUC determined from the equation where AUC = 1.84 X C0 + 4.39 X C2 + 312.66 (Keown et al 1996). Two or more AUC determinations were performed in 13 patients. The serum creatinine (Cr), age, sex, weight, CyA dose, calculated creatinine clearance (Cockcroft and Gault) and history of rejection were recorded at the time of CyA assay. Results 63 patient were studied (41 males & 22 females). The average age was 46 years (range 20‐72). The mean serum creatinine was 0.168 (range 0.07‐0.415). The C2 was the major determinant of the AUC with a correlation coefficient of 0.99 (R squared). The C0 had a weaker correlation with AUC (R squared 0.34). Serum Cr, total CyA dose, dose/kg did not correlate significantly with AUC. In individual patients who underwent multiple AUC determinations there was insufficient data to correlate with renal function. Conclusion The strong correlation between C2 and AUC suggests that a single 2 h CyA estimation is sufficient to determination the AUC using the equation AUC = 4.6 X C2 + 432. This will permit further studies of the role of CyA AUC to optimise immunosuppressive therapy without doubling the number and cost of CyA determinations.     

Neoral-to-Gengraf conversion in renal transplant recipients

OBJECTIVE: Our objective was to evaluate the safety, efficacy, and need for dosage adjustments when patients taking the Neoral formulation of cyclosporine are converted to the generic formulation, Gengraf. METHODS: From September 2001 through January 2002, patients receiving follow-up care in the renal transplant clinic at the VA Tennessee Valley Healthcare System were converted from Neoral to Gengraf based on a 1:1 dosing equivalency. Steady-state cyclosporine trough concentrations were obtained both prior to and following Neoral-to-Gengraf conversions. Patients were also monitored for changes in serum creatinine, hospitalization, cyclosporine toxicity, graft rejection, and need for further adjustment in cyclosporine regimen. RESULTS: Forty-one patients were included in data analysis. There were no differences in cyclosporine concentrations (P =.0853) or serum creatinine (P =.4469) following conversion to Gengraf. There were no reports of cyclosporine toxicity, no episodes of graft rejection, and no need for further dose adjustment related to the generic conversion. CONCLUSIONS: Neoral and Gengraf are therapeutically equivalent cyclosporine formulations, such that renal transplant recipients maintained on Neoral can be safely and effectively converted to the Gengraf formulation based on a 1:1 conversion ratio. The use of Gengraf over Neoral within the Veterans Affairs Healthcare System offers a reduced cost alternative but maintains equal efficacy and outcomes.     

Comparison of Neoral and Sandimmun for induction and maintenance immunosuppression after kidney transplantation

We compared the mean trough level/dose (L/D) ratio, mean coefficient of variation (CV) of individual patients, and graft, patient, and rejection-free survival rates of 40 renal transplant recipients receiving Neoral (CyE) with 103 consecutive renal transplant recipients receiving Sandimmun (CyA). The mean L/D ratio on the 3rd post-transplant day (16.2 vs 11.8, P < 0.04), in the 1st week (24.6 vs 16.1; P < 0.03), and 1st month (39.1 vs 28.7; P < 0.05) were higher in the CyE group. In both groups the L/D ratio improved in proportion to the duration of time post-transplant and reached a maximum in the 3rd post-transplant month. In the early post-transplant period in particular, the number of patients achieving target levels was significantly higher, and the mean dose needed to achieve target levels lower, in the CyE group. The variation in trough levels, demonstrated by the CV, was lower in the CyE group (0.41 ± 0.14) than in the CyA group (0.62 ± 0.21; P < 0.005). Actuarial 1-year patient and graft survival rates in the CyE group were 100 % and 96 %, respectively; these were similar to the 100 % and 95 % in the CyA group. The 1-year rejection-free survival rate in the CyE group was 61 % compared to 43 % in the CyA group (P < 0.02). We conclude that it is possible to obtain higher blood trough levels at lower doses by administering CyE, particularly in the early post-transplant period. The lower variability of trough levels and the higher L/D ratio in the CyE group, which are related to improved bioavailability of CyE, may explain the lower rejection rate among these patients. In this study, the microemulsion formulation of cyclosporin (CyE) was found to be more beneficial and cost-effective as induction and maintenance immunosuppression than the conventional formulation (CyA). Received: 28 January 1997 Received after revision: 13 May 1997 Accepted: 15 May 1997     

Safety and tolerability of a new oral formulation of cyclosporin A, Sandimmun Neoral, in renal transplant patients

Abstract The current therapy with Sandimmun has been improved by the development of a new oral formulation of its active ingredient, Cyclosporine A and which is called Sandimmun Neoral. This new galenical formulation is based on the microemulsion technology and offers consistent oral absorption and pharmacokinetic predictability. In two studies of a 12 weeks duration each and including 466 stable renal transplant patients and 86 new renal transplant patients it was shown that Sandimmun Neoral is as well tolerated and as safe as Sandimmun. Stable renal transplant patients currently receiving Sandimmun can safely be switched to Sandimmun Neoral on a 1:1 dose level basis. However, as a result of the more consistent absorption of Sandimmun Neoral, poor absorbers with Sandimmun will become normal absorbers and than will need a considerable dose reduction to reach the same Cyclosporine A exposure. In new renal transplant patients kidney function seems to improve better and faster when Sandimmun Neoral is given as shown by creatinine and creatinine clearance values. In the Sandimmun Neoral group less patients experienced a rejection episode and time free of rejection was longer, this may reflect a better maintenance of immunosuppression. In addition, considerably lower doses (16% on average) are required for Sandimmun Neoral to achieve comparable cyclosporine A blood trough levels and these patients are also sooner stabilized in terms of Cyclosporine a therapy.     

Renal function in renal or liver transplant recipients after conversion from a calcineurin inhibitor to sirolimus

Two Six-month pilot studies were conducted in renal (n = 17) or liver (n = 15) transplant recipients to evaluate renal function after conversion from calcineurin inhibitor (CI)- to sirolimus (SRL)-based immunosuppression. After an SRL loading dose, doses were individualized to achieve whole blood trough levels of 10-22 ng/mL. Overall, serum creatinine did not change from baseline to six months post-conversion but an improvement from 219.9 to 201.4 micromol/L at three months was noted in renal transplant recipients (p < 0.05). Another finding was a numerical increase in the mean glomerular filtration rate (GFR) from 26.8 to 33.2 mL/min/1.73 m(2) at six months among liver transplant recipients (NS). All patients survived and all grafts were functioning at the end of the study. In conclusion, renal function remained stable, with a tendency towards improvement, after abrupt conversion from CI- to SRL-based therapy in renal or liver transplant recipients with moderate renal insufficiency.     

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.     

Conversion from cyclosporine microemulsion to tacrolimus-based immunoprophylaxis improves cholesterol profile in heart transplant recipients with treated but persistent dyslipidemia: the Canadian multicentre randomized trial of tacrolimus vs cyclosporine microemulsion.

BACKGROUND: Tacrolimus improves lipid profile in renal and liver transplant recipients. The impact of conversion from cyclosporine microemulsion (Neoral) to tacrolimus (Prograf) in a large randomized study of stable heart transplant recipients with treated but persistent mild dyslipidemia is reported. METHODS: One hundred twenty-nine long-term (>or=12 months) cyclosporine microemulsion-treated heart transplant recipients with low-density lipoprotein cholesterol >2.5 mmol/liter and/or a total cholesterol/high-density lipoprotein cholesterol ratio >4 were recruited for the study. Complete lipid profile was assessed before (baseline) and after 6 months of treatment with either cyclosporine microemulsion maintenance (n=64) or tacrolimus conversion (n=65). RESULTS: At 6 months, tacrolimus-converted patients exhibited a greater decrease in total cholesterol (from 5.51 +/- 0.16 to 4.88 +/- 1.22 mmol/liter [tacrolimus], vs 5.61 +/- 1.36 to 5.38 +/- 0.87 mmol/liter [cyclosporine]; p = 0.0078). This decrease in cholesterol was caused largely by a decrease in low-density lipoprotein cholesterol (-0.41 +/- 0.54 [tacrolimus] vs -0.13 +/- 0.55 [cyclosporine]; p=0.0018). There were no changes in high-density lipoprotein cholesterol and triglyceride levels, but apolipoprotein B therapy was reduced in tacrolimus-converted vs cyclosporine-maintained patients (p=0.0003). By 6 months, 23.7% of tacrolimus- vs 6.7% of cyclosporine-treated patients met the target lipid levels for high-risk patients (p=0.0094). Conversion from cyclosporine to tacrolimus resulted in decreases in blood urea nitrogen, creatinine, and uric acid without any changes in glucose, HbA(1C), and insulin levels. CONCLUSIONS: Conversion from cyclosporine microemulsion- to tacrolimus-based immunoprophylaxis resulted in decreased cholesterol, apolipoprotein B, urea, creatinine, and uric acid without any clinically evident perturbation of glucose metabolism in stable heart transplant recipients with treated but persistent mild dyslipidemia.     

Deterioration of renal function after replacement of cyclosporine with sirolimus in five patients with severe renal impairment late after heart transplantation

A retrospective analysis of all cases when cyclosporine (CyA) was replaced with sirolimus (SIR) to avoid the renal toxicity of CyA late after heart transplant (OHT) was discontinued due to advanced renal impairment in all five heart transplant recipients (four men, 1 women; age 41 years, range 38-45; time after OHT 5 years, range 4-14). The serum creatinine level at the time of SIR introduction, which was 298 micromol/L (range 217-676), had remained stable for the 6 months prior to conversion. Target SIR trough levels were 12-20 ng/mL. In four patients the last dose of CyA was immediately followed by the first dose of SIR, whereas in one patient CyA was tapered gradually in the presence of low-dose SIR. Deterioration of renal function with signs of fluid overload and increased serum creatinine levels (Delta: 77, 33-150 micromol/L) was observed in all patients. Two patients required dialysis during SIR treatment including one case of pulmonary edema requiring emergency hemodialysis. None of four biopsies showed significant rejection. Four patients were converted back to low-dose CyA (including the two patients requiring dialysis during SIR therapy); one was maintained on mycophenolate mofetil. The creatinine level at the time of SIR discontinuation was (range 250-753) micromol/L, 448. Eventually, all patients required dialysis. In conclusion, replacement of cyclosporine with sirolimus in heart transplant recipients with severe renal impairment late after transplantation may accelerate renal failure.     

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.     

Randomized clinical trial of the effect of microemulsion cyclosporin and tacrolimus on renal allograft fibrosis

BACKGROUND: The aim of this study was to compare the effect of Neoral cyclosporin- and tacrolimus-based therapy on the development of renal allograft fibrosis (chronic allograft nephropathy; CAN) in a prospective randomized trial. METHODS: A total of 102 patients undergoing renal transplantation were randomized to immunosuppression with either microemulsion cyclosporin (Neoral; 15 mg per kg per day adjusted to whole-blood trough concentrations of 200-300 ng/ml) or tacrolimus (0.2 mg per kg per day adjusted to whole-blood trough levels of 8-15 ng/ml) in conjunction with steroids, or at a lower dose (7 mg per kg per day and 0.1 mg per kg per day respectively) with the addition of azathioprine for non-heart-beating renal transplant recipients. Renal transplant interstitial fibrosis was quantified using computerized histomorphometric measurement of picrosirius red-stained 1-year protocol renal transplant biopsies. Levels of interstitial fibrosis were compared in relation to observed efficacy and toxicity profiles of the two drugs. RESULTS: There was a significant increase in allograft interstitial fibrosis in the patients treated with Neoral compared with those given tacrolimus. There was no significant difference in the demographic characteristics between the patient groups or in the incidence of acute rejection (Neoral 36 per cent versus tacrolimus 35 per cent) or steroid-resistant rejection (both 10 per cent) between the two drugs. There was a higher incidence of insulin resistance in the tacrolimus group (post-transplant diabetes mellitus, glucose tolerance testing) but this was not statistically significant. Neoral was associated with a significant increase in total cholesterol (P = 0.030) and low-density lipoprotein (P = 0.021) levels, which persisted throughout the study period. CONCLUSION: Despite equivalent efficacy and pretransplantation risk factors for CAN, Neoral was associated with increased allograft fibrosis and significantly higher serum low-density lipoprotein cholesterol levels compared with tacrolimus.     

Substitution of conventional cyclosporin with a new microemulsion formulation in renal transplant patients: results after 1 year

BACKGROUND: A new galenic form of cyciosporin A has been developed, basedon microemulsion technology. The bioavailability of the compoundis reiativeiy independent of food intake and bile flow. It wasthe purpose of this prospective clinical trial to study thesafety of the microemulsion form of cyclosporin A. METHODS: Three hundred and two renal transplant patients, stratifiedaccording to transplant age, were switched from the conventionalto the new micro-emulsion formulation of cyclosporin A. A 1:1conversion ratio was used. Measurements included CsA levels,S-creatinine, liver enzymes, uric acid, and blood pressure.Measurements were performed at baseline and on days 4, 8, 15,29 and months 3, 6 and 12 after conversion. Dose adjustmentswere performed to achieve trough levels of 80–120 ng/ml. RESULTS: Within the 12-month observation period the cyclosporin dosewas reduced by 14.7% (from 204±60 mg/day at baselineto 174±51 mg/day after conversion, P<0.001). Acutely,i.e. by day 8, a 1:1 dose conversion resulted in a modest increaseof mean drug trough levels (from 114 ng/ml at baseline to 120ng/ml, P<0.01). This increase was accompanied by an increasein serum creatinine concentration, a decrease in calculatedcreatinine clearance, and an increase in uric acid values (P0.05).Liver enzymes remained unchanged while systolic and mean arterialblood pressure decreased (P<0.05). After 1 month, drug troughlevels had decreased to baseline (112 ng/ml) and remained thereuntil month 6. They were significantly lower after 12 months(102±33 ng/ml, P<0.001). Creatinine clearance valuesincreased to above baseline at 6 and 12 months. Within the 1-yearperiod there occurred 24 (=8%) episodes of biopsy-proven rejectionand seven episodes of cyclosporin-attributed nephrotoxicity. CONCLUSIONS: The 1:1 conversion from conventional cyclosporin A to the microemulsionformulation is efficacious and safe, but an initial dose reductionof 10% is advised in patients with trough levels in the high-normalrange.     

Comparison of microemulsion and conventional formulations of cyclosporine A in preventing acute rejection in de novo kidney transplant patients. The U.K. Neoral Renal Study Group

BACKGROUND: The microemulsion preconcentrate formulation of cyclosporine A (CsA) (Neoral) exhibits more uniform pharmacokinetics than the conventional formulation (Sandimmun; SIM). This randomized, open-label, U.K. multicenter study compared the efficacy, safety, and tolerability of Neoral and SIM in preventing acute rejection in de novo renal transplant recipients. METHODS: Adult cadaveric kidney recipients (n=293) received Neoral or SIM twice daily for 12 months. Initially identical Neoral and SIM doses were titrated, maintaining trough CsA levels within locally defined therapeutic limits. RESULTS: In the year after transplantation, acute rejection occurred in 34% of the Neoral and 47% of the SIM recipients (P=0.037). In the intent-to-treat population, fewer treatment failures (defined as acute rejection, graft loss, withdrawal, or death) occurred in the Neoral (45%) than the SIM recipients (58%) (P=0.015) and therapeutic CsA levels (> or =250 microg/L) were reached faster with Neoral than SIM (P=0.0017). Antibody treatment of refractory rejection was used slightly less in the Neoral group (Neoral: 10%; SIM: 12%). One-year patient and graft survival rates (excluding deaths with functioning grafts) were 95% and 88%, respectively, for Neoral and 96% and 89% for SIM. Both formulations were well tolerated. No differences were observed between therapies in the nature, frequency, or severity of adverse events. Neoral use was not associated with increased nephrotoxicity or excessive immunosuppression. CONCLUSIONS: Neoral reduced the incidence of acute rejection compared with SIM, without significant increases in adverse events. This was achieved without altering existing SIM protocols and was attributed to improved absorption of CsA from Neoral and less variability in whole blood CsA concentrations.     

Cicloral versus neoral: a bioequivalence study in healthy volunteers on the influence of a fat-rich meal on the bioavailability of cicloral

The bioavailability of cyclosporine a (CyA) was assessed in 2 cross-over studies with 12 healthy male volunteers each. Study A compared the bioavailability of Cicloral (test) with the microemulsion Neoral (reference) in the fasting state. Study B examined the influence of a fat-rich meal composed according to the Food and Drug Administration (FDA) recommendations on the bioavailability of Cicloral. Each volunteer received a single dose of 200 mg CyA in each period. Whole blood CyA concentrations were determined using HPLC up to 48 hours after drug administration. The pharmacokinetic parameters were determined using standard noncompartmental methods. The mean bioavailability of Cicloral compared with Neoral amounted to 83% (AUC) and 78% (Cmax), respectively. When administered after a fat-rich meal, the bioavailability of Cicloral was 121% (AUC) and 132% (Cmax) compared with fasting administration. Time to Cmax was 1.3 to 1.4 hours for both medications and modes of administration. Bioequivalence could not be proven either between Cicloral and Neoral, or between Cicloral fasting versus after a fat-rich meal. We conclude that the lower bioavailability and the influence of food on the bioavailability of Cicloral must be taken into account when switching from Neoral to the generic formulation.     

The effect of cyclosporine on mortality and renal function in living related pediatric kidney transplant recipients

The outcome, incidence of acute rejection episodes, complications and cyclosporine (CyA) induced nephrotoxicity were studied in 10 pediatric kidney transplant recipients who were grafted from one-haplotype indentical parent with immunosuppression of CyA and prednisolone (Pred). Excellent patient and graft survival could be achieved in this population with low incidences of acute rejection or serious complications as when compared with the results of azathioprine (AZ) treated pediatric patients. With a mean follow-up of 12.9 months (range 1 to 50 months), the patient survival rate was 100 per cent and the graft survival rate was 100, 84, 84 and 84 per cent at 1, 2, 3 and 4 years post transplantation, respectively. Serum creatinine levels in the group were 0.97, 1.17, 1.14 and 1.2 mg/dl at 3, 6, 12 and 24 months post transplantation, respectively. The incidence of treated acute rejection episodes was 20 per cent (2 out of 10) in the CyA-treated children, whereas it was 53 per cent (9 of 17) in the Az-treated children. Five children who had undergone transplant surgery before they were 11 years old displayed linear growth in height after their transplantation. There have been no opportunistic infections, aseptic necrosis or peptic ulcers in this group and cyclosporine nephrotoxicity has not been a serious problem in the pediatric recipients. Only 10 per cent (1 out of 10) of the recipients displayed acute nephrotoxicity and only one recipient has converted from CyA+Pred to CyA+AZ+Pred (Three drug therapy) due to persistent nephrotoxicity. Cyclosporine and prednisolone have therefore constituted a relatively safe, effective immunosuppressive regimen for pediatric renal allograft recipients. This paper was presented at the 7th international congress of pediatric nephrology.     

The Influence of Calcineurin Inhibitors on Pulse Wave Velocity in Renal Transplant Recipients

Background. Pulse wave velocity (PWV) is a marker of the arterial wall stiffness and independent cardiovascular risk factor in hemodialysis patients. Cyclosporine A (CyA) and tacrolimus (TAC) are known to differ in the influence on cardiovascular risk factors in renal transplant recipients. Recent studies suggest that CyA may decrease arterial compliance. The aim of the study was to assess the influence of CyA and TAC on the PWV and arterial wall stiffness in renal transplant recipients. Methods. The study population consisted of two groups of cadaveric renal transplant recipients, 76 patients each, matched for age, sex, blood pressure, body mass index, and length of the post-transplant follow-up. PWV between carotid and femoral artery was measured using a Complior device. Fasting blood was sampled for serum creatinine, lipid profile, uric acid, glucose, and C-reactive protein. Results. Aortic pulse wave velocity—a marker of increased arterial stiffness—was significantly higher in CyA group compared with TAC group (9.33 ± 2.10 vs. 8.54 ± 1.35, respectively; p < 0.01). Uric acid, total cholesterol, triglycerides, and LDL-cholesterol concentrations were significantly higher in CyA group. Significant correlations were found between PWV and age, systolic and diastolic blood pressure, and fasting glucose in the CyA group, but only between PWV and age in TAC group. Conclusion. CyA-based immunosuppressive therapy is associated with an unfavorable profile of cardiovascular risk factors and increased arterial stiffness in renal transplant recipients.