| Abstract|| |
Cyclosporine (CsA) is an effective immunosuppressant drug. Recently a new oral formulation, Sandimune Neoral (SIM-NOF) has been developed to overcome the problems of poor bioavailability, unpredictable blood levels and variable gastro-intestinal absorption seen with the use of traditional Cyclosporine, Sandimune (SIM). We conducted a prospective, open label crossover tolerability, efficacy and safety of SIM-NOF and (2) to compare SIM-NOF with SIM for their bioavailability, absorption pattern and consistence of 12-hour trough levels. Fourteen renal transplant recipients, with stable renal function (serum creatinine stable for more than six immediate previous months) and SIM dosages, were randomly selected for the study. Their age mean ± SD 38.2± 11.1 years, ad had completed 3.8± 2.2 years after transplantation. All patients were on triple drug immunosuppression with prednisone, azathioprine and SIM. The study consisted of an initial 12-week period, where SIM was used and cyclosporine 12-hour trough levels were monitored t least every four weeks. This was followed by a run-in period of two weeks, where a 12-hour cyclosporine profiling was done while patients were on SIM. This was followed by a 12-week period, Where SIM-NOF replaced SIM on a 1:1 dose conversion ratio. During this latter period, 12-hour trough levels (at 1,2,3,8 and 12 weeks) were measured. The doses of the SIM-NOF were adjusted to maintain blood cyclosporine trough levels at 50-180 μg/ml. On cyclosporine profiling, SIN-NOF showed a predictable and constant absorption profile peaking at two hours in all instances with steady declining levels through the following ten hours. With SIM the levels were unpredictable and erratic. The Tmax for SIM-NOF was 2.0± 0 hours and for SIM 3.7± 1.7 hours (p<0.0001). The Cmax for SIM- NOF was 2149 and for SIM 1942 (p=0.008). The 12-hour trough studies for SIM-NOF is a superior preparation to SIM in clinical practice. No specific adverse effects were observed.
Keywords: Cyclosporine, Sandimmune Neoral, Efficacy, Absorption profile.
|How to cite this article:|
Nampoory MR, Johny KV, Costandi JN, Al-Muzaire RA, Gupta RK, Nair MP. Cyclosporine Neoral: A Local Experience. Saudi J Kidney Dis Transpl 1999;10:26-30
|How to cite this URL:|
Nampoory MR, Johny KV, Costandi JN, Al-Muzaire RA, Gupta RK, Nair MP. Cyclosporine Neoral: A Local Experience. Saudi J Kidney Dis Transpl [serial online] 1999 [cited 2019 Nov 19];10:26-30. Available from: http://www.sjkdt.org/text.asp?1999/10/1/26/37298
| Introduction|| |
Cyclosporine A (CsA) is a powerful immunosuppressive agent, which is now widely used in all organ transplantation such as the kidney, liver, heart, pancreas and bone marrow. Marketed initially as Sandimmune (SIM) in 1984, its use has considerably improved graft and patient survival after renal transplantation.
The use of SIM, which is a strongly hydrophobic peptide, is associated with limitations such as a poor bioavailability, unpredictable blood levels and dietary interference with gastric absorption. A new liquid oral formulation Sandimmune Neoral (SIM-NOF) has been recently developed on the concept of microemulsion. Several clinical trials have been conducted on this new drug since 1992.
As the preparation became available in the Gulf countries, we conducted a prospective, open label crossover study of one group of patients to compare SIM and SIM-NOF in renal transplant recipients at Mubarak AlKabeer University Hospital, Kuwait.
The aim of the study were: (1) To evaluate the tolerability, efficacy and safety of the use of SIM-NOF in the stable renal transplant recipients and (2) to compare SIM-NOF with SIM for their bioavailability, absorption pattern and consistence of 12-hour trough levels.
| Patients and Methods|| |
Fifteen renal transplant recipients who had stable serum creatinine levels with a mean ± SD of 112.8 ± 32.4 µmol/L for more than six months were selected for the study. They received their renal transplant 3.8 ± 1.1 years prior to the study (range 2 to 6 years). They were ten males and five females. Their ages were 38.2 ± 11.1 years. Fourteen patients completed the study; one was excluded as she was found to be pregnant during the run in period. All patients were on triple drug immunosuppression with SIM, prednisone and Azathioprine. At the start of the study, the patients were on SIM twice daily doses. All patients were on steady dosages of SIM for the previous six months. None of the patients were on concurrent usage of any nephrotoxic drugs of other medications known to interfere with CsA absorption or metabolism.
The study consisted of an initial 12-week period, where SIM was used and Cyclosporine 12-hour trough levels were monitored at least every four weeks. This was followed by a 2-week run-in period, where SIM administration was continued. During these two weeks, all patients underwent clinical examinations, in addition to laboratory assessments of renal and liver functions and complete hemograms. CsA profiling was done while on SIM, measuring CsA blood levels at 0, 2, 4, 6, 8, 10 and 12 hours.
At the end of the run-in period, all patients were switched to oral SIM-NOF at 1:1 ratio CsA. Profiling was repeated with blood level monitoring on 2 hourly intervals over 12 hours, as was done during the run-in period for SIM. SIM-NOF was continued for the nest 12 weeks. During this period, 12-hour trough levels were repeated at 1, 2, 3, 8 and 12 weeks. The target CsA level during SIM-NOF therapy was in the range of 50-180 ng/ml, which was the same as that of SIM in each patient. Patients were also closely monitored for any adverse side effects or deterioration in renal function. Also we measured hemogram, liver functions and serum electrolytes.
Whole blood CsA level was measured using monoclonal TDX kits. The target CsA level was 50-180 ng/ml. The CsA profiling was done after ingestion of a regular breakfast. The mode of administration of SIM-NOF remained unchanged. A rise in serum creatinine of more than 20% of the baseline value coupled with a rise in CsA blood level was considered as cyclosporine toxicity and the dose of SIM-NOF was reduced and maintained.
The pharmacokinetic profiles of CsA were tested using similar doses of SIM and SIMNOF in the same patient. The peak concentration (Cmax), time to reach peak concentration (Tmax) and area under the curve (AUC) were assessed. AUC was calculated as per the linear trapezoidal method.
| Statistical Analysis|| |
Comparisons were done using Levenes' test for equality of variances. Statistical hypothesis was tested at 0.05 significant levels.
| Results|| |
CsA profiling of patients while on similar doses of SIM or SIM-NOF are shown in [Figure - 1] and [Figure - 2], respectively. The absorption and metabolic patterns were highly predictable with SIM-NOF in contrast to SIM.
The Cmax on SIM was 380 ± 133 ng/ml whereas it was 433 ± 129 on SIM_NOF (p=0.3). The Tmax of SIM-NOF was two hours in all patients with a predictable pattern of fall in blood CsA levels during the following ten hours. In contrast, Tmax of SIM was 3.7±1.72 hours in eight patients; peaking late than two hours. This difference between SIM were closely similar to those of SIM-NOF; the CsA levels in between was less predictable on SIM compared to SIM-NOF as shown in [Table - 1], [Figure - 1],[Figure - 2].
The bioavailability of CsA of SIM-NOF, as measured by AUC, was significantly superior of that of SIM (2148 ± 573 Vs 1941 ± 566, p=0.008), [Table - 2].
The CsA trough levels during the 12 weeks of SIM and the subsequent 12 weeks of SIM-NOF are shown in [Figure - 3] and [Figure - 4] respectively. The CsA trough levels were highly variable while on SIM administration.
In four patients, CsA level rose while on SIM-NOF compared to that on SIM administration, which necessitated a 20% reduction in SIM-NOF dose. No adverse clinical or laboratory events were noted during the whole study period.
| Discussion|| |
Clinical experience has shown that suboptimal levels of CsA are associated with increased incidence of acute rejection.  In addition, it has also been shown that kidney transplant recipients with poor cyclosporine bioavailability have increased incidence of graft loss. , Subjects who have higher Cmax and AUC on a single pharmacokinetic study have also been shown to have better clinical outcome.  Hence, it is essential to obtain a cyclosporine preparation with better bioavailability.
Adequate absorption is crucial for the immunosuppressive effect on CsA. Large intraindividual variability in CsA pharmacokinetics is well known with the use of SIM  . More predictable absorption, bioavailability and pattern of absorption of SIM-NOF have been recently reporte. ,
Single dose of study in healthy individual has shown an increase of 42 to 58% in AUC and 48 to 51% increase in Cmax and CsA level suing SIM-NOF compared to SIM and hence a dose conversion of 0.6 to 1.0 was suggested.  However, in clinical application in renal transplant recipients, the predose trough levels were found to be similar for both SIM and SIM-NOF. Accordingly, a 1:1 conversion ratio is recommended with careful subsequent monitoring. 
The present study showed a regular predictable pharmacokinetic profile for SIM-NOF in all patients compared to an erratic and unpredictable pattern with SIM in 78% of the patients. Furthermore, a significantly shorter Tmax and a higher Cmax with SIM-NOF compared to SIM also denote better gastrointestinal absorption of SIM-NOF.
The CsA predose trough levels, even though variable, were not significantly different for SIM and SIM-NOF. Nevertheless, AUC was significantly different for the two groups demonstrating the superiority of SIM-NOF. Current monitoring practices using predose troughs levels may need reexamination. A reduction in dose by 20%, which we could achieve in four patients, could be explained on better bioavailability and improved pharmacokinetic. However, further studies involving a larger number of patients are required to confirm this observation.
In summary, SIM-NOF produced more predictable and less variable CsA trough blood levels over a 3-month observation period compared to SIM. The pharmacokinetic 12-hour profiling of SIMNOF was strictly predictable, as shown by a higher Cmax and shorter Tmax. In addition, the drug bioavailability of SIM-NOF was superior as shown by a higher AUC.
There are tow limitations to this study. Intravenous studies were not performed and thus strict comparison on bioavailability could not be achieved. Next, the sample size was small. Within these limitations, the study has, however, re-asserted the superiority of the microemulsion form of cyclosporine in clinical use.
| Acknowledgement|| |
We thank Mr. George Varughese for the excellent secretarial assistance in preparation of this manuscript.
| References|| |
|1.||Schroeder TJ, Sridhar N, Pesce AJ, Alexander JW, First MR. Clinical correpations of cyclosporine specific and nonspecific assays in stable renal transplants, acute rejection and cyclosporine nephrotoxicity. Ther Drug Monit 1993;15:190-4. [PUBMED] |
|2.||Lindholm A, Welsh M, Alton c, Kahan BD, Demographic factors influencing cyclosporine pharmacokinetic parameters in patients with uremia: recial differences in bioavailability. Clin Pharmacol Ther 1992;52:359-71. |
|3.||Lindholm A, Welsh M, Rutzky L, Kahan BD. The adverse impact of high cyclosporine. Clearance rate in the incidences of acute rejection and graft loss. Transplantation 1993;55:985-93. |
|4.||Schoeder TJ, Hariharan S, First Mr. Variations in bioavailability of cyclosporine and relationship to clinical outcome in renal transplant subpopulations. Transplant Proc 1995;27:837-9. |
|5.||Brodehl J, Bokenkamp A, Hoyer PF, Offiner G. Long-term results of cyclosporine A therapy in children. J Am Soc Nephrol 1992;2:S246-54. |
|6.||Holt DW, Mueller EA, Kovarik JM, van Bree JB, Kutz K. the pharmacokinetics of Sandimmune Neoral: anew oral formulation of cyclosporine. Transplant Proc 1994;26(5):2935-3. |
|7.||Kahan BD, Dunn J, Fitts C, et al. The bneorla formulation: improved correlation between cyclosporine trough levels and exposure in stable renal tranaplant recipients. Transplant Proc 1994;26(5):2940-3. |
|8.||Sketris IS, Lawen JG, Beauregard Zollinger L, et al. comparison of the pharmacokinetics of cyclosporine |
|9.||Sandimmune Neoral in stable renal transplant patients. Transplant Proc 1994;26(5):2961-3. |
|10.||Kovarik JM, Mueller EA, Johnston A, Hitzenberger G, Kutz K. Bioequivalence of soft gelatin capsules and oral solution of a new cyclosporine formulation. Pharmacotherapy 1993;13:613-7. [PUBMED] |
Kaivilayil V Johny
Department of Medicine, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat, 13110
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]
[Table - 1], [Table - 2]