Comparison of pharmacokinetics of Neoral and Sandimmune in stable pediatric liver transplant recipients.

Cyclosporine (Sandimmune; Novartis Pharmaceuticals UK Ltd) is an effective immunosuppressive drug, but its lipid formulation and variable absorption may expose children to the risk of rejection during episodes of gastroenteritis after liver transplantation. Neoral (Novartis) is a microemulsified form of cyclosporine that may be better absorbed. In this study, the pharmacokinetic profiles of Neoral and Sandimmune were compared in stable children after liver transplantation to evaluate whether Neoral is more predictably absorbed. Eight children, 6 boys and 2 girls, with a mean age of 4.5 years (range, 1.2-12) were studied between 4 and 12 months after liver transplantation. Pharmacokinetic profiles were performed on each child by using the same dose (mg/kg) of Neoral or Sandimmune. Tmax, Cmax, Ctrough, and the area under the curve (AUC) were calculated and side effects were documented in children taking either drug for more than 3 months. Mean peak cyclosporine levels were higher and were achieved significantly sooner with Neoral (Cmax 790.5 +/- 216.5 ng/mL, P =.06; Tmax 1.8 +/- 1.0 hr, P =.01) than with Sandimmune (Cmax 589.4 +/- 313 ng/mL, Tmax 2.5 +/- 1.7 hr), implying more rapid and better absorption. There was no significant difference in overall drug exposure (AUC) and 12-hour trough levels between the two formulations (P >.05). Children with Roux-en-Y loop biliary anastomosis taking Neoral, however, showed greater increases in AUC (mean increase = 37%) than those with duct-to-duct anastomosis (mean increase = 16%). There was no correlation between 12-hour trough level and AUC for either Neoral (r2 = 0.48) or Sandimmune (r2 = -0.08); however, for both drugs, AUC correlated very well with the 2-hour post-dose level (r2 = 0.68 and 0.7, respectively). Hirsutism was reported in 4 of 6 children on Neoral and may be associated with higher peak levels. Neoral is more consistently absorbed than Sandimmune in children after liver transplantation and may be more effective prophylaxis against rejection. Because of the increased peak levels and drug exposure, which may influence side effects, particularly in children with Sandimmune malabsorption, we recommend a 1:0.75 dose conversion ratio in patients being converted from Sandimmune to Neoral.     

The pharmacokinetics of equoral versus neoral in stable renal transplant patients: a multinational multicenter study

We studied the pharmacokinetics (PKs) of the new generic cyclosporine formulation, Equoral capsules, after the switch from original formulation Neoral capsules in stable renal transplant patients. The study was carried out in accordance with the basic principles defined in the US 21 CFR Part 312.20 and the principles of the Declaration of Helsinki. The study included clinically stable first renal transplant patients maintained on cyclosporine with no rejection episode during the past 6 months. Hematology, biochemistry, and urine chemistry were determined on day 7, and day 21. The patients were all switched to Neoral (lot number 416MFD0601) on day 0 when the first sparse sampling PK was performed. On day 14 a 12-hour PK profile included predose, 30 minutes; 1 hour; 1 hour 30 minutes; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 8 hours; 10-hours and 12-hour samples. Cyclosporine levels were determined using a CYA kit (Abbott TDx). On day 15 the patients were switched from Neoral capsules to Equoral capsules (lot 5T111014) at an equivalent dosage (mg/mg). The second sparse sampling PK was performed on day 21 and a 12-hour PK was performed on day 28. On the morning of day 29 patients were switched from Equoral capsules to Neoral capsules at an equivalent dosage (mg/mg). Additional concentrations were measured on days -7, 18, and 35. Safety parameters were monitored at each visit. The pharmacokinetics of both formulations were equivalent. The mean AUC for Neoral and Equoral was 2856 and 2892, respectively. The ratios of LSM and the 90% confidence intervals for the in-transformed parameters (AUC o-t, AUC inf, and Cmax) of Equoral and Neoral SGC were 98% and 95%, respectively, suggesting that Equoral and Neoral SGC are bioequivalent.     

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.     

Assessment of bioequivalence of a generic cyclosporine (Equoral) by a prospective randomized controlled trial on allogeneic stem cell transplant recipients

Introduction

Bioequivalence of Equoral has been suggested by measurements of pharmacokinetic parameters in healthy volunteers and in stable renal transplant recipients, but not study in allogeneic stem cell transplant (ASCT) recipients. The aim of our study was to compare the pharmacokinetics and safety of Equoral to Neoral solution among ASCT recipients.

Patients and methods

Our open-label, two-way crossover, randomized controlled trial compared Equoral versus Neoral solutions in ASCT recipients. The 30 enrolled patients from June 2007 to November 2008 had a 7 to 14-day duration of the test period. A 10-point blood sampling from 0 to 12 hours measured Cmax (extent of absorption), tmax (rate of absorption) and AUC_0-12h (area under the concentration-time curve) calculated by the linear trapezoid rule. The study protocol was approved by the ethics committee.

Results

Median age was 26 years (range = 6-47). The mean pharmacokinetic features were: AUC_0-12h: Equoral 4162 ± 1231 ng · mL/h vs Neoral 4370 ± 1059 ng · mL/h (P = .50); Cmax: Equoral 821 ± 244 ng/mL vs Neoral 834 ± 298 ng/mL (P = .86); and tmax: 105 minutes for both formulations. Comparable toxicities and rates of graft-versus-host disease were recorded in both groups.

Conclusion

We suggest that Equoral and Neoral solution can be considered interchangeable in ASCT recipients.     

Effect of orange and tangerine juice on cyclosporine levels in renal transplant recipients

INTRODUCTION: Cyclosporine Neoral is a major immunosuppressive agent widely used in organ transplant populations. Its pharmacokinetics are influenced by various factors. The aim of this study was to investigate the effects of orange or tangerine juice on the pharmacokinetic pattern of cyclosporine Neoral among renal transplanted patients. MATERIALS AND METHODS: Ten renal transplant recipients on cyclosporine Neoral-based immunosuppressive therapy were included in this crossover controlled study. Patients were given their individualized morning dose of cyclosporine with either 250 mL water or 250 mL orange or tangerine juice; 12-hour cyclosporine pharmacokinetic investigations were performed. The three investigation days were separated by at least 7 days. RESULTS: The intake of orange juice did not have any significant influence on the area under the curve in the interval from 0 to 12 hours (AUC 0-12; 95% confidence interval [CI]: -769 to 734, P=.77), or the maximum whole blood concentration (Cmax; 95% CI: 264 to 74; P=.32). Similarly, after coadministration of cyclosporine Neoral with tangerine juice, no significant changes were observed in AUC 0-12 (95% CI: -453 to 1166; P=.28) or Cmax (95% CI: -239 to 179; P=.37). CONCLUSION: Coadministration of orange (var Tampson) or tangerine (var Unshiu) juice with cyclosporine compared with water did not influence exposure to cyclosporine in renal transplant recipients.     

Pharmacokinetics of cyclosporin in children with stable renal transplants

Fourteen children, aged between 5 and 17 years, with stable renal graft function and stable cyclosporin A (CSA) trough levels (Cmin) were studied. They had been taking CSA 12-hourly since their transplant 1.5–9 years previously, with the average dose of Neoral being 6.4 (range 4.4–8.4) mg/kg per day. CSA whole blood levels were measured at 0, 20, and 40 min, and at 1, 1.5, 2, 2.5, 3, 4, 6, and 8 h following the morning dose using the Abbott TDx fluorescence polarization immunoassay. The area under the concentration time curve (AUC), clearance adjusted for bioavailability (CL/F), and steady-state volume of distribution adjusted for bioavailability (Vss/F) were determined using model-independent pharmacokinetic analysis. Delay time (Tdel), peak concentration (Cmax), time to peak concentration (Tmax), and Cmin were also determined and correlated with AUC and other parameters. The Tdel in absorption varied from 0.3 to 1.6 (mean 0.73) h, resulting in a similarly variable time to Tmax of 1–2.4 h (mean 1.59). Tmax was related to the age of the patient (Tmax=0.027age+1.41, r ²=0.56, P<0.005). The AUC showed good correlation with Cmax (Cmax=0.25AUC+423.32, r ²=0.96, P<0.0005). Cmax appears to be a more-suitable measure of exposure to CSA than Cmin. Prediction of Tmax from the age of the child may help to overcome the problem of when to collect blood for peak levels. Received: 23 July 1998 / Revised: 4 February 2000 / Accepted: 9 February 2000     

Bioavailability of a new generic formulation of mycophenolate mofetil MMF 500 versus CellCept in healthy adult volunteers

Several studies have revealed a decreased incidence of early graft rejection with the use of mycophenate mofetil (MMF). The cost of the drug is, however, prohibitive especially in developing countries with limited resources. We compared the pharmacokinetic profile of a new MMF generic formulation (MMF 500 batch number: 06T3001; Medis Tunis) with those of Cellcept, (batch number: M1427; Hoffmann La Roche, Switzerland) in healthy volunteers. The study was double-blinded to investigator and volunteers. It had a balanced randomized, two-treatment, two-period, two-sequence, single-dose, crossover, comparative oral bioavailability design in adult healthy human volunteers. The study was designed, performed, and monitored by CRO Transmedical s.a.l International (Beirut, Lebanon) in accordance with the Basic Principals defined in the US 21 CFR Part 312.20, and the principals enunciated in the World Medical Association Declaration of Helsinki. We included nonsmoking healthy volunteers between the ages of 22 and 45 years. The subjects were admitted to the hospital one night prior to blood sampling. After volunteers received the same dinner, they were fasted overnight and for 2 hours postdosing. At 8 am each person received a single oral dose of 500 mg of either formulation. Blood samples were collected to construct the pharmacokinetic profiles as follows: 0, 0.15, 0.30, 0.45 minutes and 1, 1.15, 1.30, 2, 4, 6, 10, 12, and 24 hours. Water and food intake were the same for all volunteers during the whole study period. Following an 8-day washout period, the subjects were crossed over. Plasma mycophenolic acid concentrations were determined using a high-performance liquid chromatography validated enzyme-linked immunosorbent assay-based method (TransMedical, Beirut Lebanon). Physical examinations, hematology, urinanalysis, serum chemistry tests, and liver enzymes were performed at screening and at the end of each period. Subjects were monitored for safety and adverse events throughout the study by two physicians (one from the hospital and one from TransMedical). The Cmax, Tmax, and AUC for MMF 500 were 10.14 ng/mL, 51.82 minutes, and 18.33 ng/mL/h vs 10.94 ng/mL, 49.09 minutes, and 17.46 ng/mL/h for CellCept, respectively. The 90% confidence intervals (LSM) of Cmax, Tmax, and AUC for MMF 500 were 92.7%, 105.6%, and 105%, respectively, which is within the Food and Drug Administration (FDA)-assigned range for immunosuppressive drugs (90% to 111%). These results indicated that the products are equivalent and switchable according to FDA rulings.     

Pharmacokinetics and tolerability of 40-0-[2-hydroxyethyl]rapamycin in de novo liver transplant recipients

BACKGROUND: 40-0-[2-Hydroxyethyl]rapamycin (RAD), a novel macrolide with potent immunosuppressive and antiproliferative activities, prevents rejection in animal allotransplantation models. This phase I trial assessed the effects of bile diversion, administration route, and time after transplant on RAD pharmacokinetics after single-dose administration in de novo liver allograft recipients. The influence of RAD on cyclosporine (CsA) pharmacokinetics and the safety of RAD were also evaluated. METHODS: Twenty-six de novo liver allograft recipients were assigned to one of four treatment groups based on the presence or absence of a T tube, administration route (nasogastric or nasoduodenal), and timing of RAD administration. Patients received a single 7.5-mg RAD dose on one to three occasions in addition to CsA (Neoral) and corticosteroids. Steady-state cyclosporine profiles with and without RAD coadministration were evaluated. Results. Recipients with bile diversion demonstrated lower peak concentration (Cmax) than those without, but overall drug exposure (AUC) was not altered. Cmax and AUC were not influenced by administration route. A trend towards higher Cmax on postoperative day 3 than on postoperative day 1 was noted, although AUC was not altered. Single-dose RAD coadministration did not affect steady-state CsA pharmacokinetics. RAD was well tolerated and caused few drug-related adverse effects. RAD administration did not increase infection rates or produce clinically significant changes in laboratory parameters. Conclusions. In de novo liver transplant recipients, the overall extent of RAD absorption was not influenced by bile diversion, administration route, or time of administration. CsA pharmacokinetics were not affected by single-dose RAD coadministration. RAD capsules administered in single doses of 7.5 mg were well tolerated and safe.     

Neoral in de novo liver transplantation: Adequate immunosuppression without intravenous cyclosporine

Absorption of cyclosporine from the traditional oral formulation Sandimmune (Novartis Pharma, Basel, Switzerland) is particularly unpredictable in the early stages after liver transplantation. The absorption of cyclosporine is influenced by liver function, postoperative paralytic ileus, and graft dysfunction. Oral absorption of cyclosporine from Sandimmune is also bile dependent; cholestasis and external biliary drainage are associated with low cyclosporine absorption. Postoperative administration of intravenous Sandimmune is therefore often necessary to obtain adequate immunosuppression, despite the increased risk of renal and neurological toxicity. A microemulsion formulation of cyclosporine, Neoral (Novartis), has been developed to overcome the problems of poor and variable absorption of cyclosporine from Sandimmune. Uptake of cyclosporine from Neoral is rapid and less dependent on bile secretion so that higher peak concentrations are reached and absorption is less variable than with Sandimmune. A review of several open studies in which Neoral was administered to liver transplant patients immediately after transplantation is presented. The results suggest that the use of Neoral as a primary immunosuppressive therapy provides adequate cyclosporine trough levels, minimizing or obviating the need for intravenous cyclosporine administration. In addition, Neoral appears to reduce the risk of acute rejection episodes compared with immunosuppressive regimens involving intravenous cyclosporine. (Liver Transpl Surg 1997 Nov;3(6):571-7)     

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.     

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.     

Therapeutic equivalence and mg:mg switch ability of a generic cyclosporine microemulsion formulation (Sigmasporin Microral) in stable renal transplant patients maintained on Sandimmun Neoral

We tested a hypothesized pharmacokinetic difference between the reference (Sandimmun Neoral) and test (Sigmasporin Microral) products to prove therapeutic equivalence in an open, multiple fixed dose, one-way crossover, multicenter, and multinational study over a period of 29 days. Forty two stable renal transplant recipients maintained on Sandimmun Neoral were enrolled. Whole blood was collected at day 14 of the study at 0, 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after reference dosing and the same schedule was repeated at day 29 after switching on an mg:mg basis to the test product at day 15 of the study. Analysis of variance was performed for the pharmacokinetic parameters (area under the curve [AUC](0-12), maximum concentration [C(max)]) of cyclosporine using log-transformed values. Tolerability was assessed by vital signs, adverse events, and laboratory investigations. The 90% confidence interval (CI) test for the Ln-transformed, pharmacokinetic parameters was all within the US Food and Drug Administration acceptable range of 80% to 125%, as Ln area under the steady-state curve (AUC(ss)) was within the range of 92.56 to 103.55 and Ln C(max) was within the range of 85.73 to 103.58; the same also applied for AUC(0-4), which may be considered the area of greatest inter- and intra-patient variability. Furthermore, in line with the newly adopted recommendations of the Expert Advisory Committee on Bioavailability and Bioequivalence of Health Canada, the 90% CI for AUC(ss) was within the narrow range of 90% to 112%. No significant difference in tolerability was recorded between the two products. Sigmasporin Microral (Julphar) was found to be bioequivalent and clinically interchangeable on an mg:mg basis with Sandimmun Neoral (Novartis).     

Conversion from tacrolimus to cyclosporin in stable renal transplant patients: safety, metabolic changes, and pharmacokinetic comparison

BACKGROUND: Conversion from tacrolimus to cyclosporin has not previously been reported as routine clinical practice, but only as indicated by rejection or adverse effects. METHODS: The safety and metabolic outcome of elective conversion from tacrolimus to cyclosporin was examined in 19 recipients of cadaver renal transplants. Conversion was performed in stable patients at 3-6 months after transplantation. RESULTS: Patient and graft survival was 100% at 3 months after conversion, with no rejection episodes. Three patients have been subsequently converted back to tacrolimus, two for rejection and one for hirsutism. There were no significant changes in creatinine, urate, or blood sugar levels after conversion, but the mean plasma magnesium rose from 0.73 (0.63-0.97) to 0.82 (0.65-1) mmol/liter (P=0.037), and the mean plasma cholesterol rose from 5.2 (3.4-6.8) to 5.5 (3.8-7.6) mmol/liter (P=0.033). Pharmacokinetic profiles were measured before and after conversion, and showed that cyclosporin (Neoral) exhibited significantly less interpatient and intrapatient variability than tacrolimus, for area under the curve (AUC), maximum concentration postdose (Cmax), minimum concentration postdose (Cmin), time to maximum concentration (Tmax). CONCLUSION: This is the first study that has examined the outcome of conversion from tacrolimus- to cyclosporin-based immunosuppression in stable patients after renal transplantation. This conversion was performed without early immunological hazard, but there was a small rise in blood cholesterol levels after conversion. Pharmacokinetic studies showed cyclosporin in the form of Neoral showed less inter- and intrapatient variability than tacrolimus, although this is of uncertain clinical significance.     

Pharmacokinetics of oral cyclosporine (Neoral) in heart transplant recipients during the immediate period after surgery

Neoral cyclosporine has better absorption characteristics than the original Sandimmun formulation. This has allowed Neoral to be administered orally in circumstances where Sandimmun had been ineffective, including the postoperative phase of liver transplantation. Sampling strategies, such as the measurement of drug concentration 2 h after oral administration, have been used in a variety of settings to estimate systemic exposure to Neoral (measured as the area under the blood concentration curve (AUC) of the drug) in blood. We conducted a pilot study to determine whether Neoral could be administered orally immediately after heart transplantation and to determine which pharmacokinetic parameters reflect systemic drug exposure in this setting. Eight male patients (mean age 50 years) undergoing a first heart transplant were studied. Neoral was administered orally before surgery and at 12-h intervals via a nasogastric tube after surgery. Twelve-hour pharmacokinetic profiles were obtained on postoperative days 1, 3 and 5. Cyclosporine concentrations were measured with the Dade Behring Emit assay, which is specific for the parent drug. Drug concentrations were dose-normalised and drug exposure was measured by the AUC. Drug exposure following administration (AUC(0-12)) was low on day 1 but increased by 99% between postoperative day 1 and day 5 ( P<0.05), indicating more complete absorption of cyclosporine; exposure in the first 4 h post-dose (AUC(0-4)) increased by 126% ( P<0.01), reflecting more rapid cyclosporine absorption, and the maximum blood concentration observed increased by 137% ( P<0.05) during the same period. The correlation between the cyclosporine trough concentration and AUC(0-12) was low on all days. Due to the changing pattern of cyclosporine absorption, concentration measurements at a single time point could not accurately predict 12-h exposure to the drug on all study days. However, the drug concentration at 2 h post-dose had a high correlation with drug exposure during the first 4 h (correlation of C(2) to AUC(0-4): r(2)>0.93 on all days). Absorption of Neoral was low immediately after heart transplantation but improved substantially during the first 5 days after surgery. No single timed measurement of drug concentration reflected cyclosporine exposure; however, the 2-h concentration did provide an accurate measure of the early phase of drug absorption (AUC(0-4)). Oral administration of Neoral may result in inadequate immunosuppression immediately after heart transplantation unless it is supplemented either by intravenous cyclosporine or by the use of an induction agent.     

Mean xenograft survival of 14.6 days in a small group of hDAF-transgenic pig hearts transplanted orthotopically into baboons

INTRODUCTION: In a discordant orthotopic xenotransplantation model (pig-to-baboon) donor pigs expressing human decay accelerating factor (hDAF) as a regulator of complement activity were used to prevent hyperacute xenograft rejection (HXR). We investigated a modified immunosuppressive therapy consisting of ERL080 (Novartis Pharma AG, Base, Switzerland), cyclosporin A (Neoral), steroids, and a cyclophosphamide (CyP) induction protocol with several reduced doses to prevent acute vascular rejection (AVR). METHODS: Donor hearts were harvested from hDAF-transgenic pigs (18.8 +/- 2.6 kg, Imutran Ltd., a Novartis Pharma AG Company). Four adult baboons (25.6 +/- 2.7 kg) with high titers of xenoreactive antibodies (XAb) served as recipients. Serological and hemodynamic parameters were measured. Finally, myocardial tissue was sampled for histological and immunohistochemical examinations. RESULTS: In the first baboon, an acute graft failure occurred after 1 hour due to preservation injury. The second succumbed after 11.1 day due to an acute renal failure. The third died after 13.1 days of an ileus. The fourth baboon had continuously excellent cardiac function (mean echocardiographic ejection fraction, 69.2%), but succumbed on day 20 due to anemia. Corrected mean xenograft survival (excluding the first baboon because of a technical failure) was 14.6 +/- 2.6 days. XAb decreased after day 3 to constantly low levels (<1:64 titer) after CyP induction. White blood cell count decreased from 10.3 +/- 0.8 to 0.9 +/- 0.3 G/L after day 3. Macroscopically and histologically no typical signs of HXR or severe AVR could be detected. CONCLUSIONS: These results confirm that hDAF transgen blocks HXR in this life-supporting model. AVR was prevented by using a modified quadruple immunosuppressive drug combination (Neoral, ERL080, steroids, and several small single doses of CyP). An optimum "fine-tuning" of immunosuppression is required to achieve the best risk-benefit ratio.     

Conversion from tacrolimus to cyclosporine in stable renal transplant patients: safety, metabolic changes, and pharmacokinetic comparison

BACKGROUND: Although conversion between tacrolimus and cyclosporine has been performed when indicated for rejection or adverse effects, the safety and metabolic outcome of elective conversion from tacrolimus to cyclosporine has not previously been examined. METHODS: Conversion from tacrolimus to cyclosporine was performed in 19 recipients of cadaver renal transplants at 3-6 months after transplantation. Pharmacokinetic profiles and biochemical studies were performed three times, in steady state, before, and after conversion. RESULTS: Patient and graft survival was 100% at 3 months after conversion, with no rejection episodes. Three patients have been subsequently converted back to tacrolimus, two for rejection and one for hirsutism. There were no significant changes in creatinine, urate, or blood sugar levels after conversion, but the mean plasma magnesium rose from 0.73 (0.63-0.97) to 0.82 (0.65-1) mmol/L (P=0.037), and the mean plasma cholesterol rose from 5.2 (3.4-6.8) to 5.5 (3.8-7.6) mmol/L (P=0.033). Pharmacokinetic profiles were measured before and after conversion, and showed that cyclosporine (Neoral) exhibited significantly less interpatient and intrapatient variability than tacrolimus, for area under the curve (AUC), maximum concentration after dose (Cmax), minimum concentration after dose (Cmin), and time to maximum concentration (Tmax). CONCLUSION: This is the first study that has examined the outcome of conversion from tacrolimus- to cyclosporine-based immunosuppression in stable patients after renal transplantation. This conversion was performed without early immunological hazard, but there was a small rise in blood cholesterol levels after conversion. Pharmacokinetic studies showed that cyclosporine in the form of Neoral exhibited less inter- and intrapatient variability than tacrolimus, although this is of uncertain clinical significance.     

Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection: results of a prospective, randomized comparison of neoral and sandimmune for liver transplantation (NOF-8)

BACKGROUND: Despite two decades of use, there are limited data on the best way to administer and monitor cyclosporine (CsA) for liver transplantation. The present study was undertaken (1) to determine whether treatment with a new formulation of CsA, Neoral, would improve the results of liver transplantation; and (2) to study the relationships between pharmacokinetic parameters and clinical outcomes after transplantation. METHODS: A double-blind, randomized, comparison of Sandimmune (SIM) with Neoral (NEO) was conducted at five Canadian centers in 188 consecutive adults undergoing primary orthotopic liver transplantation. Patients were induced with intravenous CsA then switched to NEO or SIM. Dose adjustments were made daily, or as needed, to reach a target trough CsA level of 350 ng/ml in both groups. Pharmacokinetic studies were performed on days 5, 10, 15, and 16 weeks after transplantation. RESULTS: The NEO group was slightly younger, with a median age of 50 years (range: 23-70) versus 55 years (range: 24-71) for SIM (P = 0.007); otherwise the two groups were well balanced. The NEO group stopped intravenous CsA earlier (5.8+/-2.6 days vs. 8.7+/-4.7 days, P<0.0001). This group required a lower median daily oral dose (7.5 mg/kg vs. 9.0 mg/kg, P<0.01) to maintain comparable trough CsA levels. Five SIM patients, but no NEO patients, discontinued the study due to the inability to reach target trough levels of CsA within the prescribed time (P<0.05). At 4 months, there were no differences between the two groups with respect to patient survival (93% NEO vs. 91% SIM), graft survival (90% NEO vs. 86% SIM), and rejection-free survival (54.1% NEO, 51.8% SIM). The incidence of serious adverse events was also similar and did not correlate with CsA pharmacokinetic profiles. The NEO group had a higher area under the drug concentration curve for the first 6 hr after the dosing interval (AUC0-6) and peak CsA levels (Cmax). There was a strong correlation between freedom from graft rejection during the first month after transplantation and (a) AUC0-6 and (b) Cmax at days 5 and 10 after transplantation, but only in the NEO group did this reach statistical significance. In contrast, there was a poor correlation between trough CsA and graft rejection. In patients on NEO, the concentration of CsA 2 hr after dosing (C2) closely reflected AUC0-6 (r2 = 0.93), whereas there was a poorer correlation in patients on SIM (r2 = 0.73) CONCLUSIONS: Cmax and/or AUC0-6 may provide better markers than trough levels for monitoring CsA-based immune suppression after orthotopic liver transplantation. Prospective studies are underway to determine whether dosing to C2, which provides a good estimation of Cmax, can be used to take full advantage of NEO's improved absorption profile.     

Prograf Five Milligrams Versus Tacrolimus Medis in Healthy Volunteers: A Bioequivalence Study

For FDA approval, bioequivalence of a generic version of Tacrolimus must be demonstrated in a randomized, two-treatments, two-periods, two-sequences, single-dose crossover study in healthy adult volunteers. Currently there are at least 3 differents generic equivalent for Tacrolimus, that are approved by the EMA and the FDA, with a USA market share of nearly 50%. However, the market share of generic immunosuppressive drugs in the Middle East region is still very low due to the reluctance of the physician to accept Tacrolimus generics, considered to be a narrow therapeutic window drug, that are approved using the standard bioequivalence criteria of 80% to 125%. Herein we present a bioequivalence study of a new Tacrolimus generic, Tacrolimus Medis 5 mg developed by Medis Tunisia batch number 12G3003 compared with Prograf® 5 mg batch number 7202 manufactured by Astellas Toyama Co., Ltd. Japan and HIKMA Pharmaceuticals, Amman-Jordan in healthy adult volunteers using the 90%–111% criteria recommended for drugs with narrow therapeutic window. The study was, balanced, randomized, two-treatments, two-periods, two-sequences, single dose, crossover, comparative oral bioavailability study in healthy adult human volunteers. The study was carried out in accordance with the Basic Principles defined in the U.S. 21 CFR Part 312.20, the principles enunciated in the Declaration of Helsinki (World Medical Association Declaration of Helsinki). Thirty six non-smoking healthy, as determined by medical history, volunteers, 18 years and older, were included. Following randomization using a computer software (pharma solution) the volunteers were given a single oral dose of 5 milligrams following a 12 hour fast with a wash out period of 7 days. Pharmacokinetics profile with blood levels at: 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours were performed following each dose. Tacrolimus plasma level was determined using an HPLC validated method (Transmedical For Life S.A.R.L. Beirut Lebanon), for accuracy, suitability, reproducibility, precision , long-term stability and robustness. Physical examinations, hematology, urine analysis and serum chemistry tests were performed at screening and before dosing in each period and at end of the study. Volunteers were monitored for safety and adverse events throughout the study. Both products were bioequivalent at the entire pharmacokinetic parameters tested. The LSM were 95.31%–101.21% for AUC, 94.65%–101.11% for AUC0-inf, 97.15%–100.02% for C_max and 91.54%–103.75% for Half-life. Respectively all of which are within the EU and FDA approval limits (90–111%) indicating that the 2 products are equivalent and switchable.     

Microemulsion cyclosporin formulation, in contrast to the old formulation, widens the T lymphocyte subsets differences between stable and acute rejection of kidney transplants.

BACKGROUND: The new cyclosporin (CsA) formulation, Neoral, has different pharmacokinetics compared with Sandimmune (SIM). Larger area under the curve (AUC) values with equivalent trough blood values are reached when Neoral is administered at equivalent doses to SIM. Previously, we showed a great diagnostic reliability when using cytofluorometric analysis from fine-needle aspiration biopsy (FNAB) samples. We investigated possible changes brought about by Neoral on lymphocyte subsets and the repercussions on the activation score cut-off for acute rejection, defined under SIM treatment. METHODS: Of 63 patients that received SIM, 40 remained rejection-free and 23 suffered one episode of rejection. Of 52 patients that received Neoral, 38 remained rejection-free. Peripheral blood lymphocytes (PBL) and lymphocytes from FNAB taken on days 7 and 14 post-transplantation and on the first day of acute rejection were analysed by flow cytometry. RESULTS: Trough blood CsA levels were not different between SIM and Neoral treatments. Among rejection-free patients, a significant down-regulation of CD3DR and of CD8DR expression on both graft-infiltrating lymphocytes (GIL) and PBL, and significant up-regulation of na?ve T cells on GIL were observed with Neoral. These changes were followed by a significant down-regulation of the activation score with Neoral. Conversely, within the acute rejection group, the activation score was significantly higher with Neoral than with SIM. The activation score performed equally well in Neoral transplants compared with what we had reported with SIM. CONCLUSIONS: Our study indicates that Neoral elicits stronger immunosuppressive effects in stable patients, which eventually should translate into better clinical efficiency. However, when acute rejection supervenes, the treatment breakthrough seems stronger with Neoral. Cytofluorometric studies from FNAB samples showed that diagnostic reliability was maintained at a high level under Neoral therapy.