High intrapatient variability of tacrolimus exposure associated with poorer outcomes in liver transplantation |
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Authors: | Cristina Dopazo,Itxarone Bilbao,Sonia Garcí a,Concepció n Gó mez‐ Gavara,Mireia Caralt,Isabel Campos‐ Varela,Lluis Castells,Ernest Hidalgo,Francisco Moreso,Bruno Montoro,Ramó n Charco |
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Abstract: | Tacrolimus (TAC) is a dose‐dependent immunosuppressor with considerable intrapatient variability (IPV) in its pharmacokinetics. The aim of this work is to ascertain the association between TAC IPV at 6 months after liver transplantation (LT) and patient outcome. This single‐center cohort study retrospectively analyzed adult patients who underwent transplantation from 2015 to 2019 who survived the first 6 months with a functioning graft. The primary end point was the patient’s probability of death and the secondary outcome was the loss of renal function between month 6 and the last follow‐up. TAC IPV was estimated by calculating the coefficient of variation (CV) of the dose‐corrected concentration (C0/D) between the third and sixth months post‐LT. Of the 140 patients who underwent LT included in the study, the low‐variability group (C0/D CV < 27%) comprised 105 patients and the high‐variability group (C0/D CV ≥ 27%) 35 patients. One‐, 3‐, and 5‐year patient survival rates were 100%, 82%, and 72% in the high‐variability group versus 100%, 97%, and 93% in the low‐variability group, respectively (p = 0.005). Moreover, significant impaired renal function was observed in the high‐variability group at 1 year (69 ± 16 ml/min/1.73 m2 vs. 78 ± 16 ml/min/1.73 m2, p = 0.004) and at 2 years post‐LT (69 ± 17 ml/min/1.73 m2 vs. 77 ± 15 ml/min/1.73 m2, p = 0.03). High C0/D CV 3–6 months remained independently associated with worse survival (hazard ratio = 3.57, 95% CI = 1.32–9.67, p = 0.012) and loss of renal function (odds ratio = 3.47, 95% CI = 1.30–9.20, p = 0.01). Therefore, high IPV between the third and sixth months appears to be an early and independent predictor of patients with poorer liver transplant outcomes.Abbreviations- BPAR
- Biopsy proven acute rejection
- BMI
- Body mass index
- CKD‐EPI
- chronic kidney disease epidemiology collaboration
- CV
- coefficient of variation
- C0/D
- dose‐corrected concentration
- CMV
- cytomegalovirus
- eGFR
- estimated glomerular filtration rate
- HR
- hazard ratio
- HCC
- hepatocellular carcinoma
- ICU
- intensive care unit
- IPV
- intrapatient variability
- i.v.
- intravenously
- LC–MS/MS
- liquid chromatography‐ tandem mass spectrometry
- LT
- liver transplantation
- MELD
- model for end‐stage liver disease
- MMF
- mycophenolate mofetil
- NASH
- Non‐Alcoholic Steatohepatitis
- OR
- odds ratio
- PCR
- polymerase chain reaction
- SD
- Standard Deviation
- TAC
- tacrolimus
- 3–6 M
- three–six months
Study Highlights - WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
There is high intrapatient variability of tacrolimus and its correlation with liver transplantation (LT) outcomes. - WHAT QUESTION DID THIS STUDY ADDRESS?
Could the intrapatient variability of tacrolimus between months 3 and 6 post‐LT be a potential prognostic tool for poor outcomes? - WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Those patients with dose‐corrected concentration coefficient of variation greater than or equal to 27% between months 3 and 6 post‐LT have worst overall survival and impaired renal function. - HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
If we promptly identify those patients, a closer therapeutic drug monitoring program should be imperative with the possibility to make therapeutic interventions to improve outcomes. |
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