The main route of clearance for SRL is also biliary; with 91% of SRL metabolites found in feces and 2.2% in urine [21]. SRL has a longer elimination half-life of 62 h. The long half-life requires a loading dose if steady-state concentrations are to be reached quickly, but it also enables once-daily CX-5461 manufacturer SRL dosing [21]. A number of metabolites have been identified for

both SRL and EVR, but these display minimal activity [20] and [30]. EVR has 4 main metabolites: hydroxy-EVR, dihydroxy-EVR, demethyl-EVR, and the ring-opened form of EVR [18]. SRL forms demethylated, monohydroxylated, dihydroxylated, and didemethylated metabolites [20]. Intra- and inter-patient variability in both EVR and SRL exposure has been found to be moderate to high. The mean values of intra- and inter-patient variability in AUC has been determined for both EVR (27% and 31%, respectively) [26] and SRL (64% and 60%, respectively) [22] when administered with CsA and corticosteroids in de novo kidney transplant patients. Demographic factors including sex, age, or weight did not contribute to the inter-patient variability of EVR. Black patients, however, had a 20% lower exposure to EVR compared to white patients although it is unclear what role reduced bioavailability and/or increased Bcl-2 inhibitor clearance has to play in this observation. This lower exposure requires a higher dose of EVR to achieve the therapeutic range and may help to explain

the reduced efficacy that has been demonstrated in black patients in some but not all analyses [26] and [31]. The intra- and inter-patient variability in drug exposure emphasizes the need for TDM with EVR and SRL [22]. It can be seen that SRL and EVR share several pharmacokinetic characteristics, including high intra- and inter-patient variability and correlation of C0 with exposure. The main difference is the much longer half-life of SRL; this allows for

once-daily administration but may make it more difficult to manage in the event that interruption of therapy is necessary. The mTOR inhibitors and CNIs are all substrates of hepatic and intestinal CYP3A4 enzymes and P-glycoprotein. Competition for these shared biotransformation or transport pathways may interfere with the absorption or elimination of the drugs, potentially leading to clinically significant alterations in exposure when these agents are coadministered [18] and [21]. The current recommended standard oral dosage of TAC when administered with mycophenolate mofetil (MMF) and an induction agent is 0.1 mg/kg daily (administered as 2 divided doses 12 h apart). When administered over months 1 to 12, this dosage has resulted in a C0 of 4–11 ng/mL [32]. Few studies have characterized the pharmacokinetics of EVR and TAC when used in a combined immunosuppressive regimen. An open-label, exploratory study evaluated the pharmacokinetics of EVR and TAC in 8 maintenance renal transplant patients with CNI intolerance initially receiving MMF and TAC [33].