A meta-analysis to assess the safety and tolerability of two formulations of cyclosporine: sandimmune and neoral

Shah, Malay B.; Martin, Jill E.; Schroeder, T. J.; First, M. Roy

doi:10.1016/s0041-1345(98)01335-9

Cited by 7 publications

(3 citation statements)

References 15 publications

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“…This improved pharmacologic profile resulted in increased efficacy. A meta‐analysis of trials comparing Neoral with the old formulation of CsA showed a significant reduction in the risk of acute rejection in patients treated with Neoral 23. A review of the U.S. Renal Data Systems (USRDS) showed that Neoral reduced the relative risk of graft failure to 0.6 compared to the old formulation of CsA 24.…”

Section: Cyclosporine In Renal Transplantationmentioning

confidence: 99%

Cyclosporine: From Renal Transplantation to Autoimmune Diseases

Ponticelli

2005

Annals of the New York Academy of Sciences

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Over the last 20 years, cyclosporine (CsA) has been the mainstay of immunosuppression in renal transplantation. Initially, CsA was administered at high doses, which enhanced its potential nephrotoxicity. Better handling of the drug was obtained by lowering the dose, monitoring CsA concentration and renal function, and using graft biopsy in difficult cases. In the early 1990s, a new microemulsion showed better pharmacokinetics and efficacy than did the previous formulation. A few years later, evidence showed that checking blood levels 2 hours after administration was a more reliable indicator of CsA exposure than were trough blood levels. The combination with newer immunosuppressive drugs allowed further reduction in the doses of CsA to maintain stable renal allograft function and to improve long-term graft survival. CsA has largely been used in autoimmune diseases. There is concern about its nephrotoxicity, however, as in some studies control renal biopsies showed that CsA-treated patients developed progressive interstitial fibrosis. The risk of nephrotoxicity was related to the initial doses of CsA and to the increase in serum creatinine. Avoiding CsA in patients with creatinine clearance <60 mL/min and in those with uncontrolled hypertension, starting with CsA microemulsion at doses not higher than 4 mg/kg, and reducing the doses whenever serum creatinine increases to 30% or more over baseline may prevent deterioration of renal function. If these guidelines are followed, CsA may be safely used in autoimmune diseases.

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Section: Cyclosporine In Renal Transplantationmentioning

confidence: 99%

Cyclosporine: From Renal Transplantation to Autoimmune Diseases

Ponticelli

2005

Annals of the New York Academy of Sciences

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“…The more reproducible absorption and blood CsA concentrations achieved with Neoral are likely to result in the reduction in the incidence of acute rejection episodes in the early period as well as in the stable transplant recipients [21].…”

Section: The Novel Csa Neoral Formulationmentioning

confidence: 99%

Generic cyclosporine formulations: more open questions than answers

Cattaneo¹,

Perico²

2005

Transplant Int

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Summary The introduction of cyclosporine (CsA) in clinical practice has significantly improved patient and allograft survival after organ transplantation. The new microemulsion CsA formulation, Neoral, has been associated with a more reproducible absorption and a better patient outcome as compared to the old formulation Sandimmune. 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. However, growing body of evidence shows that CsA pharmacokinetics in healthy subjects is different from that of transplant patients, treated chronically with CsA. Therefore, converting patients from Neoral to the new generic formulations could be detrimental, exposing patients to increased risk of graft function deterioration and graft loss. Thus, more research and more accurate bioequivalence tests are required to address the unanswered problems dealing with the generic CsA formulations.

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“…Parameters that influence CsA absorption from the upper small intestine are the rate of bile flow, motility of the GI tract, the duration of the therapy, and concomitant food intake (Lemaire et al, 1990;Shah et al, 1998). It has been shown that meals containing large amounts of fat have a particularly pronounced effect on CsA absorption (Mueller et al, 1994a).…”

Section: Introductionmentioning

confidence: 99%

Three Generations of Cyclosporine A Formulations: An In Vitro Comparison

Thomas

Koelwel

Machei

et al. 2005

Drug Development and Industrial Pharmacy

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When the microemulsion formulation of the critical dose drug cyclosporine A (CsA) (Sandimmun Optoral) was introduced in the mid-1990s, it became clear that this new formulation improves the oral bioavailability of CsA and has a positive influence on its pharmacokinetic variability. Previous studies with the original CsA formulation (Sandimmun) showed that the size of the emulsion droplets and concomitant food intake has an effect on the absorption of CsA from the small intestine when orally administered. It was suggested that these effects might have an influence on the drugs' pharmacokinetic parameters. In this study, we focused on the two above-mentioned aspects and compared the first and second generations of CsA products (Sandimmun, Sandimmun Optoral) to generic CsA formulations by analyzing the contents of cyclosporine A gel capsules with respect to their emulsion droplet and micelle sizes using photon correlation spectroscopy (PCS). We tried to discern any differences in droplet size between different generations of CsA formulations, primarily the second and third generation, through simple physical tests. Because a high fat content food may influence the absorption of CsA, we also determined the distribution of CsA between hydrophilic and lipophilic phases using high-performance liquid chromatography analysis. It became clear that when compared under simple physical conditions, established cyclosporine formulations and new generic products show significant differences in droplet size and distribution between an aqueous phase and a high fat content food. Whether these differences are of clinical relevance remains to be investigated.

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A meta-analysis to assess the safety and tolerability of two formulations of cyclosporine: sandimmune and neoral

Cited by 7 publications

References 15 publications

Cyclosporine: From Renal Transplantation to Autoimmune Diseases

Cyclosporine: From Renal Transplantation to Autoimmune Diseases

Generic cyclosporine formulations: more open questions than answers

Three Generations of Cyclosporine A Formulations: An In Vitro Comparison

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