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.

Performance of different prediction equations for estimating renal function in kidney transplantation.

Numerous formulas have been developed to estimate renal function from biochemical, demographic and anthropometric data. Here we compared renal function derived from 12 published prediction equations with glomerular filtration rate (GFR) measurement by plasma iohexol clearance as reference method in a group of 81 renal transplant recipients enrolled in the Mycophenolate Mofetil Steroid Sparing (MY.S.S.) trial. Iohexol clearances and prediction equations were carried out in all patients at months 6, 9 and 21 after surgery. All equations showed a tendency toward GFR over-estimation: Walser and MDRD equations gave the best performance, however not more than 45% of estimated values were within +/-10% error. These formulas showed also the lowest bias and the highest precision: 0.5 and 9.2 mL/min/1.73 m2 (Walser), 2.7 and 10.4 mL/min/1.73 m2 (MDRD) in predicting GFR. A significantly higher rate of GFR decline ranging from -5.0 mL/min/1.73 m2/year (Walser) to -7.4 mL/min/1.73 m2/year (Davis-Chandler) was estimated by all the equations as compared with iohexol clearance (-3.0 mL/min/1.73 m2/year). The 12 prediction equations do not allow a rigorous assessment of renal function in kidney transplant recipients. In clinical trials of kidney transplantation, graft function should be preferably monitored using a reference method of GFR measurement, such as iohexol plasma clearance.