Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival

Gallagher, H.; Sarwar, Ghulam; Tse, T.; Sladden, Timothy M.; Hii, Esmond; Yerkovich, Stephanie T.; Hopkins, Peter; Chambers, Daniel C.

doi:10.1016/j.healun.2015.05.028

Cited by 44 publications

(52 citation statements)

References 37 publications

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“…This socalled intrapatient variability (IPV) is defined as the fluctuation in Tac blood concentrations within an individual over a certain period of time during which the Tac dose is left unchanged (for an indepth review of Tac IPV please see reference [45]). A high Tac IPV is considered a risk factor for poor long-term outcomes after kidney transplantation, and similar findings have been reported after liver [46] and lung transplantation [47]. The first evidence for the clinical importance of Tac IPV was obtained by Borra et al who found that the within-patient variability in Tac is a significant risk factor for reaching a composite end point consisting of graft loss, biopsyproven chronic allograft nephropathy and 'doubling in plasma creatinine concentration in the period between 12 months posttransplantation and last follow up [48].…”

Section: Intrapatient Variabilitysupporting

confidence: 74%

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

Andrews

Winter

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

111

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Introduction: Tacrolimus (Tac) is the cornerstone of immunosuppressive therapy after solid organ transplantation and will probably remain so. Excluding belatacept, no new immunosuppressive drugs were registered for the prevention of acute rejection during the last decade. For several immunosuppressive drugs, clinical development halted because they weren't sufficiently effective or more toxic. Areas covered: Current methods of monitoring Tac treatment, focusing on traditional therapeutic drug monitoring (TDM), controversies surrounding TDM, novel matrices, pharmacogenetic and pharmacodynamic monitoring are discussed. Expert opinion: Due to a narrow therapeutic index and large interpatient pharmacokinetic variability, TDM has been implemented for individualization of Tac dose to maintain drug efficacy and minimize the consequences of overexposure. The relationship between predose concentrations and the occurrence of rejection or toxicity is controversial. Acute cellular rejection also occurs when the Tac concentration is within the target range, suggesting that Tac whole blood concentrations don't necessarily correlate with pharmacological effect. Intracellular Tac, the unbound fraction of Tac or pharmacodynamic monitoring could be better biomarkers/tools for adequate Tac exposure -research into this has been promising. Traditional TDM, perhaps following pre-emptive genotyping for Tac-metabolizing enzymes, must suffice for a few years before these strategies can be implemented in clinical practice. ARTICLE HISTORY

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Section: Intrapatient Variabilitysupporting

confidence: 74%

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

Andrews

Winter

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

111

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“…12,13,16,19,20,24 TA B L E 5 Demographic factors associated with CV > 30% from venipuncture in kidney subjects found a significant relationship (R 2 = 0.93) with a Passing and Bablok fit of y = 1.00x -0.23 (95% CI slope, 0.91-1.08; intercept, −0.69-0.3). However, none of the methods confirm medication ingestion with certainty.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical use of tacrolimus is further complicated by experiences of high intrapatient variability (IPV) with some patients experiencing fluctuation in trough levels even when the dose is left unchanged. [20][21][22][23][24] Lack of adherence to the prescribed immunosuppressive regimen is also associated with poor long-term outcomes. [1][2][3][4][5][6][7][8][9][10] It is increasingly clear that high tacrolimus IPV is associated with poor long-term outcomes.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14][15][16][17][18][19] Evidence is more limited for other organs but outcomes appear to be similar in small series of liver, heart, and lung transplant recipients. [20][21][22][23][24] Lack of adherence to the prescribed immunosuppressive regimen is also associated with poor long-term outcomes. 25,26 Despite this significant risk, rates of nonadherence remain high with estimates up to 70%.…”

Section: Introductionmentioning

confidence: 99%

“…Medication Scale (BAASIS) questionnaire to assess adherence as a secondary outcome 71,72. The first 6 months following transplant is complicated by drug interactions, changes in clinical status, and frequent tacrolimus dose changes that may increase CV but have not been consistently associated with poor longterm outcomes 20,23. Both studies were limited by the time period studied (<6 months posttransplant).…”

mentioning

confidence: 99%

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Assessment of tacrolimus intrapatient variability in stable adherent transplant recipients: Establishing baseline values

Leino

King

Jiang

et al. 2019

American Journal of Transplantation

126

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The purpose of this study was to determine the intrapatient (within the same patient) variability of tacrolimus in adherent patients. Daily tacrolimus trough levels were obtained at home using dried blood spot technology in kidney and liver transplant recipients. Patients were randomized to receive 3 formulations of tacrolimus, each for two 1-week periods. Adherence was monitored by patient diary, pill counts, and use of the Medication Event Monitoring System (MEMS). Variability was quantified as the coefficient of variation (CV). Comparison of CV between groups was by independent t test or one-way ANOVA as appropriate. The population was found to be adherent with a rate of 99.9% with a mean interval between the evening and morning dose of tacrolimus of 11.86 hours. The median CV for the entire population was 15.2% (range 4.8%-110%). There were no differences in CV by allograft type or tacrolimus formulation. The multivariate analysis did not identify any demographic characteristics associated with a CV > 30%. In a highly adherent population, tacrolimus did not display high intrapatient variability. Given the association between IPV and poor allograft outcomes, future studies are needed to quantitate the influence of adherence and establish target IPV goals. K E Y W O R D S clinical research/practice, compliance/adherence, immunosuppressant -calcineurin inhibitor, immunosuppression/immune modulation, kidney transplantation/nephrology, liver transplantation/hepatology, tacrolimus | 1411 LEINO Et aL.

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Post‐Transplant Phase: Issues in the Early Postoperative Period

Mackintosh,

Hopkins

2023

Textbook of Transplantation and Mechanical Support for End‐Stage Heart and Lung Disease

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Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival

Abstract: Background: Erratic tacrolimus blood levels are associated with liver and kidney graft failure. We

Cited by 44 publications

References 37 publications

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

Assessment of tacrolimus intrapatient variability in stable adherent transplant recipients: Establishing baseline values

Post‐Transplant Phase: Issues in the Early Postoperative Period

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