title: Clinical pharmacokinetics of tacrolimus in rescue therapy after renal transplantation.
abstract: Tacrolimus, a potent new immunosuppressive drug, was introduced for rescue 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 mumol/l preceded conversion to tacrolimus. Tacrolimus rescue therapy started 73 +/- 9 months after transplantation, the follow-up was 8 +/- 1 months. Outcome, pharmacokinetics, and side-effects were analyzed. Patient survival was 100% on tacrolimus therapy. Graft survival was 88% after 3 months, and 70% after 8 months. Serum creatinine remained stable during the observation period (Crea after 8 months: 271 +/- 26 mumol/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 window 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 variability in interindividual tacrolimus dose was noted. Last cyclosporine dose was a good predictor of required tacrolimus dose after 1 month (r = 0.88; p < 0.001). Overall, 82 adverse events were noted, of which 29 (35%) were associated with high trough levels (> 10 ng/ml). In contrast, 3 patients with trough levels < 4 ng/ml had ongoing rejection. Blood pressure and routine laboratory data remained unchanged. Steroid dose could be tapered from 12 +/- 2 to 5 +/- 0.3 mg/day (p < 0.02). Gingival hyperplasia and hirsutism improved after conversion. We conclude: Tacrolimus conversion for rescue therapy after renal transplantation is efficient and safe with target trough levels between 5 -8 ng/ml. Frequent drug monitoring is necessary, especially within the first month after conversion. Previous cyclosporine dose can be used as a guideline for starting dose.
authors.affiliation: Department of Internal Medicine-Nephrology, Universitätsklinikum Charité, Humboldt University, Berlin.
authors.forename: K
authors.initials: K
authors.lastname: Budde
authors.forename: L
authors.initials: L
authors.lastname: Fritsche
authors.forename: I
authors.initials: I
authors.lastname: Mai
authors.forename: S
authors.initials: S
authors.lastname: Bauer
authors.forename: S
authors.initials: S
authors.lastname: Smettan
authors.forename: J
authors.initials: J
authors.lastname: Waiser
authors.forename: T
authors.initials: T
authors.lastname: Hofmann
authors.forename: I
authors.initials: I
authors.lastname: Hauser
authors.forename: P
authors.initials: P
authors.lastname: Reinke
authors.forename: H H
authors.initials: HH
authors.lastname: Neumayer
mesh_terms: D000328:Adult; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus