PMID- 27259059
OWN - NLM
STAT- MEDLINE
DCOM- 20171117
LR  - 20240407
IS  - 1536-3694 (Electronic)
IS  - 0163-4356 (Print)
IS  - 0163-4356 (Linking)
VI  - 38
IP  - 5
DP  - 2016 Oct
TI  - Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic 
      Modeling to Evaluate Sirolimus Drug Exposure-Response Relationships in Renal 
      Transplant Patients.
PG  - 600-6
LID - 10.1097/FTD.0000000000000313 [doi]
AB  - BACKGROUND: Sirolimus, an immunosuppressive agent used in renal transplantation, 
      can prevent allograft rejection. Identification of the therapeutic index (the 
      ratio of minimum toxic concentration to minimum therapeutic concentration) for 
      immunosuppresants is necessary to optimize the care of patients and set standards 
      for bioequivalence evaluation of sirolimus products. However, the therapeutic 
      index for sirolimus has been inconsistently defined, potentially because of 
      inconsistencies in sirolimus exposure-response relationships. METHODS: The 
      authors used retrospective therapeutic drug monitoring data from the electronic 
      health records of patients treated in a tertiary health care system from 2008 to 
      2014 to (1) develop a population pharmacokinetic (PK) model, (2) use the model to 
      simulate sirolimus concentrations, and (3) characterize the exposure-response 
      relationship. Using Wilcoxon rank-sum and Fisher exact tests, the authors 
      determined relationships between sirolimus exposure and adverse events (AEs) 
      (anemia, leukopenia, thrombocytopenia, hyperlipidemia, and decline in renal 
      function) and the composite efficacy end point of graft loss or rejection. 
      RESULTS: The developed 2-compartment population PK model showed appropriate 
      goodness of fit. In a late-phase (>12 months), postrenal transplant population of 
      27 inpatients, the authors identified statistically significant relationships 
      between 83 simulated peak and trough sirolimus concentrations and outcomes: graft 
      loss or rejection (P = 0.018) and decline in renal function (P = 0.006), 
      respectively. CONCLUSIONS: Use of therapeutic drug monitoring results and PK 
      modeling permitted correlation of sirolimus concentrations with graft loss or 
      rejection and decline in renal function. However, the method was limited in its 
      assessment of other AEs. To better evaluate sirolimus exposure-response 
      relationships, the method should be applied to a larger sample of newly 
      transplanted patients with a higher propensity toward AEs or efficacy failure.
FAU - Zimmerman, Kanecia O
AU  - Zimmerman KO
AD  - *Duke Clinical Research Institute, Duke University School of Medicine, Durham, 
      North Carolina; Departments of daggerPediatrics and double daggerMedicine, Duke University School 
      of Medicine, Durham, North Carolina;  section signDivision of Pharmacotherapy and 
      Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North 
      Carolina, Chapel Hill, North Carolina; and  paragraph signOffice of Generic Drugs, US Food and 
      Drug Administration, Silver Spring, Maryland.
FAU - Wu, Huali
AU  - Wu H
FAU - Greenberg, Rachel
AU  - Greenberg R
FAU - Guptill, Jeffrey T
AU  - Guptill JT
FAU - Hill, Kevin
AU  - Hill K
FAU - Patel, Uptal D
AU  - Patel UD
FAU - Ku, Lawrence
AU  - Ku L
FAU - Gonzalez, Daniel
AU  - Gonzalez D
FAU - Hornik, Christoph
AU  - Hornik C
FAU - Jiang, Wenlei
AU  - Jiang W
FAU - Zheng, Nan
AU  - Zheng N
FAU - Melloni, Chiara
AU  - Melloni C
FAU - Cohen-Wolkowiez, Michael
AU  - Cohen-Wolkowiez M
LA  - eng
GR  - K23 HD083465/HD/NICHD NIH HHS/United States
GR  - U01 FD004858/FD/FDA HHS/United States
GR  - K23 NS085049/NS/NINDS NIH HHS/United States
GR  - KL2 TR001115/TR/NCATS NIH HHS/United States
GR  - HHSN275201000003I/HD/NICHD NIH HHS/United States
GR  - K12 HD043494/HD/NICHD NIH HHS/United States
GR  - UL1 TR001117/TR/NCATS NIH HHS/United States
GR  - HHSN275201000003C/AA/NIAAA NIH HHS/United States
GR  - HHSN272201500006C/AI/NIAID NIH HHS/United States
GR  - R01 HD076676/HD/NICHD NIH HHS/United States
GR  - T32 HD043029/HD/NICHD NIH HHS/United States
GR  - HHSN272201300017C/AI/NIAID NIH HHS/United States
GR  - HHSN272201300017I/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Ther Drug Monit
JT  - Therapeutic drug monitoring
JID - 7909660
RN  - 0 (Immunosuppressive Agents)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Aged
MH  - *Drug Monitoring
MH  - *Electronic Health Records
MH  - Female
MH  - Humans
MH  - Immunosuppressive Agents/adverse effects/pharmacokinetics
MH  - *Kidney Transplantation
MH  - Male
MH  - Middle Aged
MH  - *Models, Biological
MH  - Retrospective Studies
MH  - Sirolimus/adverse effects/blood/*pharmacokinetics
PMC - PMC5025355
MID - NIHMS790126
EDAT- 2016/06/04 06:00
MHDA- 2017/11/29 06:00
PMCR- 2017/10/01
CRDT- 2016/06/04 06:00
PHST- 2016/06/04 06:00 [entrez]
PHST- 2016/06/04 06:00 [pubmed]
PHST- 2017/11/29 06:00 [medline]
PHST- 2017/10/01 00:00 [pmc-release]
AID - 10.1097/FTD.0000000000000313 [doi]
PST - ppublish
SO  - Ther Drug Monit. 2016 Oct;38(5):600-6. doi: 10.1097/FTD.0000000000000313.