Indications:Graft rejection prophylaxis in 50 patients undergoing kidney transplantation.
Patients:64 patients. Phase 1: 5 male patients (mean age 22 years) on hemodialysis awaiting transplantation. In phase 2 in 59 renal transplant recipients, 29 group A patients, 23 male, 6 female (mean age 34.8 years) received Sandimmun plus KET, and 28 group B patients, 26 male, 2 female (mean age 36.4 years) received Sandimmun plus diltiazem. 2 dropouts from group A. Mean duration of follow up for Group A was 238.6 ± 152.4 and 22.3 ± 133.1 days for Group B.
TypeofStudy:Phase 1 and randomized phase 2 study determining the efficacy and safety of low-dose ketoconazole (KET, 50 mg) in reducing the dose and cost of Sandimmun in renal allograft candidates and recipients.
DosageDuration:2 mg/kg in 2 divided doses for 7 days in Phase 1. 4 mg/kg daily in Group A and 8 mg/kg daily in Group B with a mean duration of 238.6 ± 152.4 days in Phase 2.
Results:In phase 1, the AUC of Sandimmun before starting KET was 1581.8 ± 484 ng.h/ml. Following addition of 50 mg of KET, the mean AUC of Sandimmun increased to 4946 ± 1006 ng.h/ml (p<0.01). With the addition of 100 mg of KET, in AUC further rise was not statistically significant (p=ns). In phase 2, two patients were excluded from Group A, one due to leukopenia contraindicating azathioprine treatment and 1 developed duodenal ulcer requiring treatment with omeprazole. Mean serum creatinine values at the last follow-up was lower among patients who received KET (1.6 ± 0.5 mg vs 2.1 ± 1.6 mg, p=0.06). Patient graft survival, number of rejection episodes, infectious complications, alanine aminotransferase elevation, posttransplant diabetes, and hyperlipidemia were comparable in both groups (p=NS). The mean Sandimmun levels in both groups were similar (p=ns). At the last follow-up, the mean dose of Sandimmun was 2.4 mg/kg/day in patients who received KET compared to 4.4 mg/kg/day in group B (p>0.001). The total costs of treatment per patient year in Group A and Group B were US $1,618.40 vs US $2,787.20, respectively, a 42% cost reduction.
AdverseEffects:infectious complications, ALT elevation, posttransplant diabetes, hyperlipidemia
AuthorsConclusions:In summary, administration of low-dose ketoconazole (50 mg) resulted in a threefold rise in the AUC of CyA in patients on hemodialysis. In renal transplant recipients, co-administration of 50 mg ketoconazole with CyA reduced the cost of immunosuppression by 42%.
FreeText:In Phase 1, patients received Sandimmun along with blood transfusion to prevent sensitization. On day 7, blood sampling was obtained for Sandimmun assay at 1,3, and 5 hours after dosing. Blood sampling for Sandimmun assay was repeated with 50 mg or 100 mg KET using the same dose of Sandimmun. In phase 2, Group A received Sandimmun and KET 50 mg from day minus 7, and azathioprine (1 mg/kg) daily from day minus 2 and increased to 2 mg/kg/day on the day of transplantation. Prednisolone 20 mg daily was started from the day of transplantation, with the dose tapered from 3 months onwards in both groups. Group B received Sandimmun from day minus 7 and azathioprine (1 mg/kg/day) from day minus 2 and increased to 1.5 mg/kg from the day of transplantation. Diltiazem (60 mg) thrice a day was added to augment Sandimmun level. Target Sandimmun level in Group A were 150 to 250 ng/ml, and 100 to 150 ng/ml for the first 2 months and after 2 months, respectively. In Group B, target levels were 200 to 300 ng/ml and 100 to 200 ng/ml. The dose of azathioprine was adjusted according to the leukocyte count. Rejection episodes were treated with methylprednisolone (20 mg/kg/day) for 3 days, and steroid-unresponsive rejection episodes were treated with anti-CD3 monoclonal antibodies. Sandimmun levels were measured by Cloned Enzyme Donor Immunoassay (CEDIA). The total cost of immunosuppression and cost of treatment per year was calculated. The results were expressed as mean (SD). Area under the time concentration curve (AUC) of Sandimmun was determined by the using the formula of Gaspari et al.
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