PMID- 24861504
OWN - NLM
STAT- MEDLINE
DCOM- 20150305
LR  - 20211203
IS  - 1878-5492 (Electronic)
IS  - 0966-3274 (Linking)
VI  - 31
IP  - 1
DP  - 2014 Jun
TI  - Focus on mTOR inhibitors and tacrolimus in renal transplantation: 
      pharmacokinetics, exposure-response relationships, and clinical outcomes.
PG  - 22-32
LID - S0966-3274(14)00039-2 [pii]
LID - 10.1016/j.trim.2014.05.002 [doi]
AB  - 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.
CI  - Copyright (c) 2014 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Shihab, Fuad
AU  - Shihab F
AD  - University of Utah School of Medicine, Salt Lake City, UT, USA. Electronic 
      address: fuad.shihab@hsc.utah.edu.
FAU - Christians, Uwe
AU  - Christians U
AD  - University of Colorado Denver, Aurora, CO, USA.
FAU - Smith, Lonnie
AU  - Smith L
AD  - University of Utah Health Care Transplant Center, Salt Lake City, UT, USA.
FAU - Wellen, Jason R
AU  - Wellen JR
AD  - Washington University School of Medicine Barnes-Jewish Hospital, Saint Louis, MO, 
      USA.
FAU - Kaplan, Bruce
AU  - Kaplan B
AD  - University of Arizona College of Medicine, Tucson, AZ, USA.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20140524
PL  - Netherlands
TA  - Transpl Immunol
JT  - Transplant immunology
JID - 9309923
RN  - 0 (Calcineurin Inhibitors)
RN  - 0 (Immunosuppressive Agents)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - Calcineurin Inhibitors/administration & dosage/pharmacokinetics
MH  - Everolimus
MH  - Humans
MH  - Immunosuppressive Agents/*administration & dosage/pharmacokinetics
MH  - *Kidney Transplantation
MH  - Sirolimus/*administration & dosage/*analogs & derivatives/pharmacokinetics
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Tacrolimus/*administration & dosage/*pharmacokinetics
OTO - NOTNLM
OT  - Calcineurin inhibitors
OT  - Pharmacokinetics
OT  - Renal transplantation
OT  - Tacrolimus
OT  - Therapeutic drug monitoring
OT  - mTOR inhibitors
EDAT- 2014/05/28 06:00
MHDA- 2015/03/07 06:00
CRDT- 2014/05/28 06:00
PHST- 2014/02/19 00:00 [received]
PHST- 2014/05/09 00:00 [revised]
PHST- 2014/05/15 00:00 [accepted]
PHST- 2014/05/28 06:00 [entrez]
PHST- 2014/05/28 06:00 [pubmed]
PHST- 2015/03/07 06:00 [medline]
AID - S0966-3274(14)00039-2 [pii]
AID - 10.1016/j.trim.2014.05.002 [doi]
PST - ppublish
SO  - Transpl Immunol. 2014 Jun;31(1):22-32. doi: 10.1016/j.trim.2014.05.002. Epub 2014 
      May 24.