A new water-free microemulsion formulation of Cyclosporine-A (CsA) (Neoral(tm)) has been introduced to minimize the irregular bioavailability of this drug when given for GVHD prophylaxis. Aim of the study was to evaluate the Neoral(tm) pharmacokinetic in allo-BMT patients early after transplantation. Eighteen patients aged over 18 were enrolled into the study. Prophylaxis for acute GVHD consisted on i.v. CsA ( 1 mg/kg/day over 24 hours c.i.) and MTX. When patients were able to eat normally, usually between day 20 and 30, they were shifted to the oral CsA administration and after 4 days, a 12 hours CsA pharmacokinetic profile was measured by HPLC. Three consecutive control patients received Sandimmune(tm) 10 mg/kg/day, 5 patients received 7.5 mg/kg/day and 10 patients 5 mg/kg/day of Neoral(tm) in two divided doses. Neoral(tm) showed reproducible concentration-time profiles characterized by a smooth and faster rise to the Cmax value without any secondary peak. The increase of Neoral(tm) from 5 to 7.5 mg/kg/day was associated with a proportional increase of area under the curve ( AUC ) (4776 + 1084 vs. 7746 ±2006 ng/ml h). Ctrough ( 186 ±80 vs 348 ±90 ng/ ml ) and Cmax (1027 ±203 vs. 15141231 ng/m)). In all patients to whom 7.5 mg/kg/day of Neoral(tm) were given, the serum creatinine remained normal (0.95 ±0.06 mg/dl) and the Ctrough levels were always above 200 ng/ml which may be considered safe to minimize the risk of acute GVHD. This observation was prospectively validated in ten additional patients in which the dose of 7.4 + 0.5 mg/kg/day of Neoral(tm) allowed to obtain mean Ctrough levels of 513 ±244 ng/ml in the absence of significant renal toxicity. Because AUC is the most appropriate parameter to evaluate the real exposure to CsA we investigated whether a limited three point sampling strategy taken early after CsA dosing (at 0, 1, and 3 h) could predict the AUC. The predicted AUC calculated by this approach was accurate (4879 ± 1242 ng/ml h after 5 mg/kg/day and 7445 ±1364 ng/ml h after 7.5 mg/kg/day) and not statistically different from the AUC calculated by multiple sampling (4776 ±1084 ng/ml h after 5 mg/kg/day and 7746 ±2006 ng/ml h after 7.5 mg/kg/day). In conclusion the use of 7.5 mg/kg/day of Neoral(tm) may represent a safe approach, resulting in appropriate CsA trough levels and GVHD prophylaxis. The AUC evaluation by a limited number of samples could he used to prevent CsA over exposure related toxicity.
|Issue number||11 PART II|
|Publication status||Published - 2000|
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