High Intrapatient Variability of Tacrolimus Exposure in the Early Period After Liver Transplantation Is Associated With Poorer Outcomes

Rayar, Michel; Tron, Camille; Jézéquel, Caroline; Beaurepaire, Jean Marie; Petitcollin, Antoine; Houssel‐Debry, Pauline; Camus, Christophe; Verdier, M. C.; Dehlawi, Ammar; Lakéhal, M.; Desfourneaux, Véronique; Meunier, Bernard; Sulpice, Laurent; Bellissant, Éric; Boudjéma, Karim; Lemaître, F.

doi:10.1097/tp.0000000000002052

Cited by 58 publications

(77 citation statements)

References 21 publications

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“…16,17,19,23,24,63 Our data showing that more than 75% of the weekly CVs were less than 25% strengthen the evidence that values above this range should begin to elicit concern as they vary from the The current study is unique in its ability to minimize many suspected cofounders. 16,17,19,23,24,63 Our data showing that more than 75% of the weekly CVs were less than 25% strengthen the evidence that values above this range should begin to elicit concern as they vary from the The current study is unique in its ability to minimize many suspected cofounders.…”

Section: Discussionsupporting

confidence: 64%

“…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%

“…[16][17][18][19]23,24 Second, additional information is needed regarding the contribution of the individual factors altering tacrolimus IPV. Coefficient of variation (CV) is the most commonly reported measure of IPV with cutoffs, often simply selected as the median value for the population, ranging from 14.9% to 40% in previous retrospective studies.…”

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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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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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Intrapatient Variability of Tacrolimus Exposure in Solid Organ Transplantation: A Novel Marker for Clinical Outcome

Kuypers

2019

Clin Pharma and Therapeutics

136

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The calcineurin-inhibitor tacrolimus provides an acceptable balance between prevention of allograft rejection and drug-related adverse effects, making it the standard of care in all types of solid organ transplantation for the last two decades. Recent data have demonstrated that high intra-patient variability (IPV) in tacrolimus pre-dose trough concentrations has deleterious effects on allograft survival. The underlying mechanisms by which a high tacrolimus IPV shortens allograft survival are acute and chronic rejection, donor-specific anti-HLA antibodies and progressive fibrotic damage to the graft. Modifiable causes of high tacrolimus IPV include medication non-adherence, drug interactions, nutritional interferences and concurrent diseases. Recognizing high tacrolimus IPV as an important prognostic risk factor after solid organ transplantation requires understanding of the definitions, the use of correct diagnostic metrics and methodology. Therapeutic interventions aimed at reducing tacrolimus IPV are targeted on improving medication non-adherence, avoiding or adjusting drug interactions, drug dosing assists and educational support of recipients.

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Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

2020

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Background Tacrolimus therapy in solid organ transplant (SOT) recipients is challenging due to its narrow therapeutic window and pharmacokinetic variability both between patients and within a single patient. Intrapatient variability (IPV) of tacrolimus trough concentrations has become a novel marker of interest for predicting transplant outcomes. The purpose of this review is to evaluate the association of tacrolimus IPV with graft and patient outcomes and identify interventions to improve IPV in SOT recipients. Methods A systematic review of the literature was performed using PubMed and Embase from database inception to September 20, 2020. Studies were eligible only if they evaluated an association between tacrolimus IPV and transplant outcomes. Both pediatric and adult studies were included. Measures of variability were limited to standard deviation, coefficient of variation, and time in therapeutic range. Results Forty‐four studies met the inclusion criteria. Studies were published between 2008 and 2020 and were observational in nature. Majority of data were published in adult kidney transplant recipients and identified an association with rejection, de novo donor specific antibody (dnDSA) formation, graft loss, and patient survival. Evaluation of IPV‐directed interventions was limited to small preliminary studies. Conclusions High tacrolimus IPV has been associated with poor outcomes including acute rejection, dnDSA formation, graft loss, and patient mortality in SOT recipients. Future research should prospectively explore IPV‐directed interventions to improve transplant outcomes.

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High Intrapatient Variability of Tacrolimus Exposure in the Early Period After Liver Transplantation Is Associated With Poorer Outcomes

Abstract: A high CV of TAC concentrations was found to be predictive of TAC-related toxicity and poorer survival.

Cited by 58 publications

References 21 publications

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

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

Intrapatient Variability of Tacrolimus Exposure in Solid Organ Transplantation: A Novel Marker for Clinical Outcome

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

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