CLINICAL PHARMACOKINETICS OF TACROLIMUS IN RESCUE THERAPY AFTER RENAL-TRANSPLANTATION

Tacrolimus, a potent new immunosuppressive drug, was introduced for re scue therapy in 25 renal transplant recipients with ongoing rejection (n = 24) or severe cyclosporine toxicity (n = 1). A highly significant (p < 0.001) rise in serum creatinine from 138 +/- 14 (3 months before conversion) to 295 +/- 26 mu mol/l preceded conversion to tacrolimus. Tacrolimus rescue therapy started 73 +/- 9 months after transplantati on, the follow-up was 8 +/- 1 months. Outcome, pharmacokinetics, and s ide-effects were analyzed. Patient survival was 100% on tacrolimus the rapy. Graft survival was 88% after 3 months, and 70% after 8 months. S erum creatinine remained stable during the observation period (Crea af ter 8 months: 271 +/- 26 mu mol/l). Starting with an initial dose of 9 .6 +/- 0.3 mg/day (0.14 +/- 0.01 mg/kg/day) we could reduce tacrolimus dose to 6.0 +/- 0.9 mg/day (0.09 +/- 0.02 mg/kg/day; p < 0.001) after 1 month. Tacrolimus trough levels were adjusted to a therapeutic wind ow of 5 - 8 ng/ml. We had to perform 3.4 +/- 0.5 dose adjustments per patient mainly within the first month after conversion (70%). A high v ariability in interindividual tacrolimus dose was noted. Last cyclospo rine dose was a good predictor of required tacrolimus dose after 1 mon th (r = 0.88; p < 0.001). Overall, 82 adverse events were noted, of wh ich 29 (35%) were associated with high trough levels (> 10 ng/ml). In contrast, 3 patients with trough levels < 4 ng/ml had ongoing rejectio n. Blood pressure and routine laboratory data remained unchanged. Ster oid dose could be tapered from 12 +/- 2 to 5 +/- 0.3 mg/day (p < 0.02) . Gingival hyperplasia and hirsutism improved after conversion. We con clude: Tacrolimus conversion for rescue therapy after renal transplant ation is efficient and safe with target trough levels between 5 - 8 ng /ml. Frequent drug monitoring is necessary, especially within the firs t month after conversion. Previous cyclosporine dose can be used as a guideline for starting dose.