Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure-Response Relationships in Renal Transplant Patients.
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.



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.



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.



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.
*Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina; Departments of †Pediatrics and ‡Medicine, Duke University School of Medicine, Durham, North Carolina; §Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina; and ¶Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland.
Kanecia O
KO
Zimmerman
Huali
H
Wu
Rachel
R
Greenberg
Jeffrey T
JT
Guptill
Kevin
K
Hill
Uptal D
UD
Patel
Lawrence
L
Ku
Daniel
D
Gonzalez
Christoph
C
Hornik
Wenlei
W
Jiang
Nan
N
Zheng
Chiara
C
Melloni
Michael
M
Cohen-Wolkowiez
D000328:Adult; D000368:Aged; D016903:Drug Monitoring; D057286:Electronic Health Records; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012189:Retrospective Studies; D020123:Sirolimus / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D020123:Sirolimus