title: Focus on mTOR inhibitors and tacrolimus in renal transplantation: pharmacokinetics, exposure-response relationships, and clinical outcomes.
abstract: Mammalian target of rapamycin (mTOR)-inhibitor-containing immunosuppressive regimens have been developed as part of calcineurin inhibitor (CNI) minimization/withdrawal strategies for renal transplant recipients, with the goal of avoiding CNI-associated nephrotoxicity. This review focuses on the pharmacokinetic interactions and exposure-response relationships of mTOR inhibitors and tacrolimus (TAC), the most widely used CNI. We also discuss key randomized clinical studies that have evaluated use of this combination in renal transplantation. Pharmacokinetic studies have shown that mTOR inhibitors, everolimus (EVR) and sirolimus (SRL), have a large intra- and inter-patient variability in drug exposure, and narrow therapeutic windows (trough levels [C0] 3-8 ng/mL and 5-15 ng/mL, respectively). Consequently, routine therapeutic drug monitoring of EVR and SRL is recommended to optimize efficacy and minimize toxicity in individual patients. As there is a good correlation between C0 and area under the curve (AUC), C0 can be used as a convenient and reliable measure of mTOR drug exposure. Clinical data on the use of EVR or SRL in TAC minimization strategies in renal transplantation are limited. Available evidence suggests that treatment with EVR allows early and substantial TAC minimization when used with basiliximab induction and corticosteroids, to achieve good renal function without compromising efficacy or safety. However, data comparing this combination with other regimens are lacking. Results with SRL are more mixed. SRL in combination with reduced TAC has been shown to provide less nephrotoxicity than the SRL/standard TAC combination, with comparable efficacy and safety. However, this approach has been shown to be inferior to other regimens in terms of patient/graft survival and biopsy-proven acute rejection (vs MMF/TAC) as well as renal function (vs MMF/TAC and SRL/MMF). Further studies are needed to define the therapeutic window for TAC when used in combination with mTOR inhibitors, evaluate EVR/reduced TAC versus other regimens, assess long-term outcomes, and determine efficacy and safety in high-risk patients.
authors.affiliation: University of Utah School of Medicine, Salt Lake City, UT, USA. Electronic address: fuad.shihab@hsc.utah.edu.
authors.forename: Fuad
authors.initials: F
authors.lastname: Shihab
authors.affiliation: University of Colorado Denver, Aurora, CO, USA.
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.affiliation: University of Utah Health Care Transplant Center, Salt Lake City, UT, USA.
authors.forename: Lonnie
authors.initials: L
authors.lastname: Smith
authors.affiliation: Washington University School of Medicine Barnes-Jewish Hospital, Saint Louis, MO, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Wellen
authors.affiliation: University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Kaplan
mesh_terms: D065095:Calcineurin Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016030:Kidney Transplantation; D020123:Sirolimus / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D016559:Tacrolimus
keywords: Calcineurin inhibitors; Pharmacokinetics; Renal transplantation; Tacrolimus; Therapeutic drug monitoring; mTOR inhibitors