Influence of delayed initiation of cyclosporine on everolimus pharmacokinetics in de novo renal transplant patients.
We quantified the influence of delayed initiation of cyclosporine on everolimus pharmacokinetics in order to provide dosing guidance for kidney transplant patients. In a randomized multicenter study, 56 de novo kidney transplant patients received everolimus, basiliximab, corticosteroids and either immediate (n = 40) or delayed (n = 16) initiation of cyclosporine based on renal function. Everolimus and cyclosporine predose blood levels (Cmin) were obtained over the first 3 months post-transplant. Everolimus Cmin averaged 9-11 ng/mL in the immediate cyclosporine group over the first 3 months. In the delayed cyclosporine group, average everolimus Cmins were significantly lower by 2.9-fold in the absence vs. presence of cyclosporine: 2.9 +/- 2.8 vs. 8.3 +/- 3.7 ng/mL (p < 0.001). Likewise, the within-patient ratio of everolimus Cmins in the presence/absence of cyclosporine averaged 2.9 (range, 0.7-5.6). Both everolimus and cyclosporine blood concentrations need to be monitored in kidney transplant patients with delayed graft function during the period when cyclosporine is withheld and shortly after its initiation. Dosing of everolimus needs to be adjusted to take into account an average threefold increase in everolimus exposure when cyclosporine is added to the regimen.
Kovarik
John M
JM
Novartis Pharmaceuticals, Basel, Switzerland. john.kovarik@pharma.novartis.com
Dantal
Jacques
J
Civati
Giovanni
G
Rizzo
Gaetano
G
Rouilly
Marisel
M
Bettoni-Ristic
Olga
O
Rordorf
Christiane
C
D016572:Cyclosporine / Q000097:blood / Q000494:pharmacology*; D000068338:Everolimus; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects*; D016030:Kidney Transplantation; D020123:Sirolimus / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus