Conversion from Sandimmune to Neoral in renal allograft recipients

Abstract

Although cyclosporine (CsA) has been clearly established as an effective immunosuppressant in reducing rejection in solid organ transplantation, intraindividual and interindividual variability in its pharmacokinetics (PK) are major limiting factors in its optimal use. The development of the microemulsion formulation of CsA, Neoral (NEO) (Sandoz, East Hanover, NJ), with better bioavailability and more predictable PK parameters offers the promise of a more reliable immunosuppressant for use in clinical transplantation and has prompted conversion of many stable renal allograft recipients formerly on the conventional formulation, Sandimmune (SIM) (Sandoz, East Hanover, NJ), to NEO therapy. In the present study, 125 stable renal allograft recipients were converted from SIM to NEO therapy in three phases and underwent evaluation of renal function and trough CsA levels and abbreviated pharmacokinetic parameters with conversion. Conversion from twice daily SIM to twice daily NEO led to increased trough CsA levels (14.3%) and a 26.3% increase in CsA exposure as measured by area under the time curve and average CsA levels, (AvCsA), without any adverse impact on renal function. On the other hand, conversion from once daily SIM to twice daily NEO was associated with a 4.9% rise in serum creatinine and was associated with a 58.5% rise in trough CsA levels after conversion. In a third cohort of patients with underlying liver dysfunction and at risk for CsA nephrotoxicity following conversion to NEO, conversion from once daily SIM to once daily NEO was not associated with renal dysfunction despite a 27.2% increase in trough CsA levels. Patients experiencing high AvCsA levels and the greatest rise in trough CsA and AvCsA levels after conversion were at highest risk for renal dysfunction from CsA nephrotoxicity. Thus, conversion protocols designed to maintain trough CsA levels at the preconversion level with subsequent NEO dose adjustments to achieve optimal AvCsA levels are likely to avert CsA nephrotoxicity secondary to increased CsA exposure. Despite the increase in CsA levels after conversion, the prospect of more reliable immunosuppression with NEO is an adequate impetus for conversion of patients from the conventional formulation. Nevertheless, NEO dose adjustments based on trough CsA levels and/or abbreviated PK profiles, as used in the present study, are likely to be necessary in optimizing NEO therapy in clinical transplantation. Copyright © 1999 by W.B. Saunders Company.