Long-term pharmacokinetic study of the novel combination of tacrolimus and sirolimus in de novo renal allograft recipients.
It was recently shown in two randomized studies that combining sirolimus (rapamycin) and tacrolimus is very efficient in renal transplantation. However, little is known about the long-term pharmacokinetics of this combination. We performed simultaneous AUC measurements (area under the concentration curves) of sirolimus and tacrolimus at 1, 3, and 12 months posttransplantation in nine de novo recipients treated with this drug combination to characterize the evolution of the pharmacokinetics of both drugs and to investigate possible interactions between the two compounds. Patients were treated with a standard-dose tacrolimus or with a reduced-dose tacrolimus in combination with sirolimus and corticosteroids. This long-term pharmacokinetic study has shown that when sirolimus is combined with tacrolimus, dose changes of sirolimus are reflected by pharmacokinetic exposure parameters. Patients taking a low dose of sirolimus in combination with a standard dose tacrolimus might require sirolimus dose increments over time to maintain constant exposure to sirolimus. Further prospective dose-controlled studies are necessary to investigate a possible effect of a standard-dose tacrolimus on long-term sirolimus bioavailability and/or metabolism. Dose reductions of tacrolimus in both study groups were reflected by concordant decreasing pharmacokinetic exposure parameters, which illustrates the common clinical practice of reducing the dose of calcineurin inhibitor as time elapses after transplantation.
Kuypers
D R J
DR
Department of Nephrology and Renal Transplantation, University Hospital Leuven, Leuven, Belgium. Dirk.kuypers@uz.kuleuven.ac.be
Claes
K
K
Evenepoel
P
P
Maes
B
B
Vanrenterghem
Y
Y
D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D020123:Sirolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus