Increasing tacrolimus time-in-therapeutic range is associated with superior one-year outcomes in lung transplant recipients

Ensor, Christopher R.; Iasella, Carlo J.; Harrigan, Kate M.; Morrell, Matthew R.; Moore, Cody A.; Shigemura, Norihisa; Zeevi, Adriana; McDyer, John F.; Venkataramanan, Raman

doi:10.1111/ajt.14723

Cited by 39 publications

(50 citation statements)

References 19 publications

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“…These observations were consistent with the findings from previous kidney transplant and lung transplant analyses, which used the TTR to characterized tacrolimus exposure (11,12). Notably, we did not find any difference in mean tacrolimus trough level between the high and low TTR groups.…”

Section: Discussionsupporting

confidence: 92%

“…The warfarin TTR cut-off value was arbitrarily determined as 75% (10) or was recommended by European guidelines as being 70% or greater (18). Two studies investigating the use of tacrolimus TTR also arbitrarily set the TTR threshold as 30% in lung transplant (11) or 60% in kidney transplant (12). Although they found that increasing tacrolimus TTR was associated with improved clinical outcomes, the optimal TTR was not determined.…”

Section: Discussionmentioning

confidence: 99%

“…TTR is a validated method for assessing effective warfarin therapy and has been used as a tool to risk stratifying (9,10). Limited studies have investigated the use of TTR in transplantation, but a low tacrolimus TTR was associated with significantly increased acute cellular risk in lung transplants (11) and de novo donor-specific antibodies (dnDSAs) in kidney transplants (12). These facts indicated that the tacrolimus TTR might have potential as a prognostic indicator in organ transplantation, but evidence of its impact on the long-term outcomes of living kidney transplants is lacking.…”

Section: Introductionmentioning

confidence: 99%

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Increasing Time in Therapeutic Range of Tacrolimus in the First Year Predicts Better Outcomes in Living-Donor Kidney Transplantation

et al. 2019

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Background:The aim of the present study was to investigate the impact of time in therapeutic range TTR on long-term outcomes of living kidney transplants. Methods:We included 1,241 living kidney transplants and randomized them into development and validation cohorts with a ratio of 2:1. The tacrolimus TTR percentage was calculated by linear interpolation with a target range (5-10 ng/ml months 0-3, 4-8 ng/ml months 4-12). The optimal TTR cutoff was estimated by the receiver operating characteristic curve analysis on the basis of acute rejection (AR) within 12 months in the development cohort. Outcomes were analyzed between patients with high TTR and low TTR in the development and validation cohorts, respectively. The TTR was also compared with other tacrolimus measures.Results: The optimal TTR cutoff value was 78%. In the development cohort, patients with TTR > 78% had significantly higher rejection-and infection-free survival. TTR < 78% was an independent risk factor for AR (OR: 2.97, 95%CI: 1.82-4.84) and infection (OR: 1.55, 95%CI: 1.08-2.22). Patient and graft survival were significantly higher in those with TTR>78%, and TTR<78% was associated with graft loss (OR: 3.2, 95%CI: 1.38-7.42) and patient death (OR: 6.54, 95%CI: 1.34-31.77). These findings were confirmed in the validation cohort. Furthermore, we divided all included patients into a high and low TTR group. TTR was more strongly associated with patient and graft survival than mean level, standard deviation, and intrapatient variability (IPV). Conclusions:Increasing the TTR of tacrolimus in the first year was associated with improved long-term outcomes in living kidney transplants, and TTR may be a novel valuable strategy to monitor tacrolimus exposure.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increasing Time in Therapeutic Range of Tacrolimus in the First Year Predicts Better Outcomes in Living-Donor Kidney Transplantation

et al. 2019

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“…In order to optimize its efficacy and minimize the occurrence of adverse events, therapeutic drug monitoring (TDM) is regularly performed in clinical practice on the basis of trough concentration (C0) levels that are determined before the next dose of tacrolimus . C0 has been selected as a measure of systemic exposure that correlates with clinical outcome (graft rejection and tacrolimus toxicity) . However, C0‐based therapeutic ranges in children are defined based on empirical adaptation of the doses according to the C0 from adult clinical data …”

mentioning

confidence: 99%

“…(1) C0 has been selected as a measure of systemic exposure that correlates with clinical outcome (graft rejection and tacrolimus toxicity). (3) However, C0-based therapeutic ranges in children are defined riva et al…”

mentioning

confidence: 99%

Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients

et al. 2019

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Tacrolimus is the cornerstone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to characterize the clinical, pharmacological, and genetic variables associated with systemic tacrolimus exposure in pediatric liver transplant patients. De novo transplant patients with a survival of more than 1 month were considered for inclusion and were genotyped for cytochrome P450 3A5 (CYP3A5). Peritransplant clinical factors and laboratory covariates were recorded retrospectively between 1 month and 2 years after transplant, including alanine aminotransferase (ALT), aspartate aminotransferase, hematocrit, and tacrolimus predose steady‐state blood concentrations collected 12 hours after tacrolimus dosing. A linear mixed effect (LME) model was used to assess the association of these factors and the log‐transformed tacrolimus dose‐normalized trough concentration (logC0/D) levels. Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients who matched the original population. The developed LME model described that logC0/D increases with increases in time after transplant (β = 0.019, 95% confidence interval [CI], 0.010‐0.028) and ALT values (β = 0.00030, 95% CI, 0.00002‐0.00056), whereas logC0/D is significantly lower in graft CYP3A5 expressers compared with nonexpressers (β = −0.349, 95% CI, −0.631 to −0.062). In conclusion, donor CYP3A5 genotype, time after transplant, and ALT values are associated with tacrolimus disposition between 1 month and 2 years after transplant. A better understanding of tacrolimus exposure is essential to minimize the occurrence of an out‐of‐range therapeutic window that may lead to adverse drug reactions or acute rejection.

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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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Increasing tacrolimus time-in-therapeutic range is associated with superior one-year outcomes in lung transplant recipients

Cited by 39 publications

References 19 publications

Increasing Time in Therapeutic Range of Tacrolimus in the First Year Predicts Better Outcomes in Living-Donor Kidney Transplantation

Increasing Time in Therapeutic Range of Tacrolimus in the First Year Predicts Better Outcomes in Living-Donor Kidney Transplantation

Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients

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

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