HOW TO CONVERT FROM TRADITIONAL CYCLOSPORINE TO THE MICROEMULSION FORMULATION IN STABLE RENAL-TRANSPLANT PATIENTS

How to convert from traditional cyclosporine (CsA) to the microemulsio n formulation in stable renal transplant patients is still a matter of debate. The present study was designed to evaluate the effects of cha ngeover from traditional Sandimmune to Neoral formulation at two dose- ratio conversions on CsA pharmacokinetics, safety and tolerability par ticularly in terms of renal function. Thirty outpatients regularly fol lowed at our Clinical Research Center were randomized to 1:1 or 1:0.75 dose-ratio conversion and assigned to the two groups according to a c omparable renal function and time post-transplant. Patients underwent CsA pharmacokinetic evaluation and renal function measurements (GFR an d RPF) before, at day 15, and at month 6 after conversion to Neoral fo rmulation. More consistent CsA concentration-time profiles with Neoral than traditional formulation were obtained at the two time points of evaluation after conversion. At 1:1 dose-ratio conversion an increased absorption rate, reflected by a shorter time to maximum blood CsA con centration (T-max), and a greater bioavailability, as shown by an incr ease in the peak CsA concentration (C-max) and the 12-h exposure to dr ug defined by the area under the time-concentration curve (AUC(0-->12h )) was found 15 d and 6 months after conversion to Neoral formulation. A similar AUC as compared with traditional Sandimmune was observed in those patients randomized to receive a 25% lower dose of Neoral formu lation. All of patients defined as 'low' absorbers became 'high' absor bers as early as 15 d after conversion to Neoral formulation at 1:1 or 0.75 dose-ratio regimen. Overall mean GFR was unchanged in both conve rsion regimens during the 6 months of follow-up. However, there was a tendency to lower GFR even in some patients randomized to 1:0.75 conve rsion but mostly in those with 1:1 conversion. A limited sampling stra tegy utilizing three blood samples (0, 1, 3 h post-dosing of Neoral fo rmulation) provided an excellent correlation with actual drug exposure (r = 0.977). Enhanced CsA absorption with the microemulsion formulati on results in increased drug exposure that may reduce GFR in some pati ents who undergo 1:1 dose-ratio conversion. The Neoral formulation tha t permits a more effective, consistent, and predictable absorption of CsA may represent a great advantage in order to prevent acute and poss ibly chronic rejections. Efforts have to be made to find optimal thera peutic range and dosing schedule for this new formulation, which may b e facilitated by using the limited sampling approach to predict AUC af ter only three-point sampling.