Therapeutic drug monitoring of sirolimus: effect of concomitant immunosuppressive therapy and optimization of drug dosing.
Sirolimus (SRL) is a new immunosuppressant which shares a common metabolic pathway with several other immunosuppressive agents. This leads to potential pharmacokinetic interactions that might affect SRL blood levels with relevant clinical consequences. As a validated laboratory, 2658 SRL trough samples (corresponding to 495 kidney transplant recipients treated with different immunosuppressive regimens) from more than 40 Italian Transplant Units were analyzed. We found that dose-normalized SRL trough levels were significantly higher in patients treated with cyclosporine (CsA) and SRL (4.15 +/- 2.23 ng/mL/mg SRL), compared with patients treated with mycophenolate mofetil (MMF) and SRL (3.26 +/- 1.86 ng/mL/mg SRL; p < 0.01) or with MMF, steroids and SRL (2.52 +/- 1.73 ng/mL/mg SRL; p < 0.01). Mean intra- and interpatient variabilities were 19% and 47%, respectively. Both parameters are significantly affected by the time postsurgery, with the first week post transplantation being associated with the greatest variability. As additional analysis, a simple dose-adjustment formula has been proposed as a useful tool to guide SRL dose changes. The proposed equation has been able to predict SRL concentration after a dose change in 73% of the tested samples. These findings suggest that different immunosuppressants significantly interfere with SRL bioavailability. Strategies aimed at reducing variability in SRL exposure may have a positive clinical impact.
Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo - Mario Negri Institute for Pharmacological Research, Bergamo, Italy. dcattaneo@marionegri.it
Dario
D
Cattaneo
Simona
S
Merlini
Marisa
M
Pellegrino
Fabiola
F
Carrara
Stefania
S
Zenoni
Stefano
S
Murgia
Sara
S
Baldelli
Flavio
F
Gaspari
Giuseppe
G
Remuzzi
Norberto
N
Perico
D000465:Algorithms; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000379:methods*; D016014:Linear Models; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors; D014180:Transplantation / Q000379:methods*
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus