This review examines recent data on the combined use of mTOR inhibitors and CNIs, with a particular focus on TAC, the most widely used CNI. Pharmacokinetic interactions, exposure–response relationships, and key randomized clinical studies using concentration-controlled dosing of these agents Rapamycin are reviewed. The oral bioavailability of mTOR inhibitors is low (14% for SRL and 20% for EVR) [19]. SRL and EVR are both metabolized extensively by cytochrome P (CYP)-450 3A in the liver and intestines, and affected by the different activities

of the drug efflux pump P-glycoprotein, which leads to the low bioavailability observed with these drugs [18] and [20]. In renal transplant patients receiving escalating single oral doses of SRL (3–21 mg/m2) in combination with CsA and corticosteroids, the maximum concentration (Cmax) http://www.selleckchem.com/products/abt-199.html ranged between 14 and 344 μg/L, and was reached (tmax) in 0.5 to 3 h [21]. In renal transplant patients receiving single oral doses of EVR (0.25 to 25 mg) in combination with CsA and corticosteroids, Cmax was found to be between 2.3 and 179 μg/L and reached in 1 to 2.2 h

[18]. Unlike dosing with SRL, however, where the dose correlates only modestly with either Cmax or with area under the curve (AUC) [21] and [22], EVR displays dose-proportional pharmacokinetics with rapid absorption leading to attainment of peak blood concentrations within 1–2 h after oral dosing [18]. Demographic factors, such as sex, age, or body weight do not affect the pharmacokinetics of EVR or SRL in adults [23] and [24]. With EVR, steady state is reached within 4 days with an accumulation in blood levels of 2-

to 3-fold compared with the exposure after the first dose [19] and [25]. In de novo renal transplant recipients receiving EVR, CsA, and corticosteroids, steady-state Cmax, C0, and AUC showed a dose-proportional increase. This steady-state, before dose-proportional effect was maintained over 1 year [23]. Importantly, the predose C0 of EVR correlated well with AUC over the year-long study. This demonstrates that C0 provides a simple, reliable index for the TDM of EVR [23] and [26]; a similar relationship has been observed for SRL [20], [21] and [22]. As over 75% of EVR and 94% of SRL in blood is sequestered into erythrocytes, whole-blood samples are appropriate for measuring systemic levels and for TDM [18] and [21]. Around 98% of EVR is excreted as metabolites in the bile and the remainder in the urine. EVR has an elimination half-life of approximately 30 h [19]. Prescribing information recommends EVR be administered twice daily (bid) in transplant recipients, mainly because of the CsA/EVR interaction described in the following section; however, preliminary evidence in renal transplant recipients suggests similar efficacy (e.g.