Effects of calcineurin inhibitors on sirolimus pharmacokinetics during staggered administration in renal transplant recipients.
OBJECTIVE
To compare the effects of different calcineurin inhibitors on sirolimus pharmacokinetics during long-term, staggered administration in kidney transplant recipients. Design. Randomized, open-label, parallel-group trial.


METHODS
A medical center and one of its teaching hospitals in Taiwan.


METHODS
Twenty-two de novo kidney transplant recipients.


METHODS
Patients received cyclosporine microemulsion or tacrolimus capsules twice/day in combination with once-daily sirolimus solution and corticosteroids. Sirolimus was administered 6 hours after the morning dose of cyclosporine or tacrolimus. After receiving a 6-mg loading dose of sirolimus, participants received sirolimus 2 mg/day for at least 7 days. Neither the cyclosporine nor the tacrolimus dosage was adjusted for at least 3 days before and during blood sampling for pharmacokinetic profiling.


RESULTS
One patient dropped out because of trimethoprim-sulfamethoxazole-related hepatotoxicity. We observed no differences between the two patient groups in terms of their demographic data, renal and liver function, or dosage of sirolimus during the study. During multiple-dose administration, the area under the whole-blood concentration-time curve and the peak and trough concentrations of sirolimus in the cyclosporine group were, respectively, 1.46 (95% confidence interval [CI] 1.21-1.71), 1.42 (95% CI 1.08-1.76), and 1.42 (95% CI 1.09-1.76) times higher than those of the tacrolimus group, even though sirolimus was administered 6 hours after the other agents.


CONCLUSIONS
Sirolimus pharmacokinetics may change significantly when calcineurin inhibitors are switched, even with staggered administration, which may not completely prevent a drug interaction between cyclosporine and sirolimus solution.
Wu
Fe-Lin Lin
FL
College of Medicine, National Taiwan University; Department of Pharmacy, National Taiwan University Hospital, Taipei. flwu@ha.mc.ntu.edu.tw
Tsai
Meng-Kun
MK
Chen
Russel Rhei-Long
RR
Sun
Shao-Wen
SW
Huang
Jin-Ding
JD
Hu
Rey-Heng
RH
Chen
Kuo-Hsin
KH
Lee
Po-Huang
PH
D000328:Adult; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D065095:Calcineurin Inhibitors; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus