Do we have the same clinical results with Neoral® and Equoral® treatment in kidney transplant recipients? A pilot study

Cyclosporine (CsA) is characterized by a narrow therapeutic index, significant side effects, and major efforts have been devoted to individualize CsA dosing based on pharmacokinetic parameters, to minimize the toxicity and improve the risk-to-benefit ratio [1]. One of the challenges in CsA management is the poor variable and unpredictable absorption associated with a great intraand inter-patient variability with a higher risk of acute and chronic rejection incidence, and eventually health care costs [2,3]. Thus, the variable oral CsA bioavailability represents a biopharmaceutical risk factor and deserves particular attention when new formulations are used. The new microemulsion CsA formulation, Neoral (Novartis, Basel, Switzerland), has been associated with a more reproducible absorption and a better patient outcome compared with the old formulation Sandimmune (Novartis, Basel, Switzerland). Recently, several generic CsA formulations have been tested as bioequivalent to Neoral . Bioequivalence tests have been performed in selected groups of young, healthy male volunteers usually in single dose studies, and then extended to completely different population, such as transplant recipients. A growing body of evidence shows that CsA pharmacokinetics in healthy subjects is different from that of transplant patients, treated chronically with CsA. Then, it appears that such a treatment could be detrimental, exposing patients to increased risk of graft function deterioration and graft loss [4]. The incidence of biopsy proven acute rejections at 6 months in de novo adult kidney transplant recipients was found significantly higher in patients who received Gengraf (Abbott) compared with those who received Neoral [5]. On the other hand, a few studies in stable [6–8] and the only one in de novo kidney transplant recipients [9] showed that Equoral (Ivax, Opava, Czech Republic) could be used as an alternative treatment to Neoral . Thus, more research and more accurate bioequivalence tests are required to address the unanswered problems dealing with the generic CsA formulations. We compared the pharmacological properties and the outcome at 6 months of treatment with Neoral versus Equoral (Ivax) in de novo kidney transplant recipients at our transplant unit. Since the beginning of the year 2006, Equoral has become available on our market. Hence, in our pilot study, we retrospectively evaluated 16 living related (LR) kidney transplant recipients in the year 2003 (Neoral group) and 15 LR patients transplanted during the year 2006 (Equoral group). All patients received an induction therapy with methylprednisolone (2 · 500 mg – at the day before and at the operation) and Daclizumab (Zenapax , Roche, Basel, Switzerland) in five doses. The maintaining triple immunosuppression consisted of: prednisolone, Cyclosporine A (dose adjustment according to the C2 levels) and mycophenolate mofetil (Cellcept ). The database consisted of the average dose of CyA during the first month and up to the sixth month after transplantation and C2 cyclosporine levels from the patients’ records. Graft function was followed as a surrogate of the serum creatinine levels at 1 and 6 months after transplantation. The number and treatment of acute rejections (AR) (clinically or biopsy proven) were obtained from the patients’ flow charts. A pulse corticosteroids was administered whenever an increase in serum creatinine >20% or decrease in urine output for two consecutive days was observed. The clinical and biochemical data for analysis were obtained at the time of transplantation as well as at 1 and 6 months after transplantation. Results are expressed as mean values ± SD. An unpaired two-tailed Student t test was used to examine differences in mean values between the groups. Chi square analysis was used to compare the categorical variables. A P-value < 0.05 was assumed significant. The statistical program used was SPSS for windows, release 13 (SPSS, Chicago, IL, USA). The groups were matched for the demography of mean age, gender and body weight for the Neoral and Equoral group, respectively (Table 1). None of the patients had diabetes, or active hepatitis B or C. The average dose of Neoral tended to be lower (borderline of significance) up to the first and was significantly lower up to the sixth month in comparison with the Equoral treatment. The