Intra-patient variability in tacrolimus exposure: Causes, consequences for clinical management

Shuker, Nauras; Gelder, Teun van; Hesselink, Dennis A.

doi:10.1016/j.trre.2015.01.002

Cited by 187 publications

(244 citation statements)

References 81 publications

Supporting

Mentioning

236

Contrasting

Unclassified

Order By: Relevance

“…There are several other studies also demonstrating that high tacrolimus variability, measured either by standard deviation or %CV, increases the risk of acute rejection and poor graft outcomes. 9, 11, 13 However, none of these studies assessed the impact of tacrolimus variability on racial disparities. Thus, the results of our investigation are confirmatory with regards to the impact of tacrolimus variability on posttransplant outcomes in the overall population and are novel with regards to its impact on disparities for AAs.…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation

Taber

Fleming

et al. 2017

Transplantation

View full text Add to dashboard Cite

Background Low tacrolimus concentrations have been associated with higher risk of acute rejection, particularly within African-American (AA) kidney transplant recipients; little is known about intrapatient tacrolimus variabilities impact on racial disparities. Methods Ten year, single-center, longitudinal cohort study of kidney recipients. Intrapatient tacrolimus variability was assessed using the coefficient of variation (CV) measured between 1 month posttransplant and the clinical event, with a comparable period assessed in those without events. Pediatrics, nontacrolimus/mycophenolate regimens and nonrenal transplants were excluded. Multivariable Cox regression models were used to analyze data. Results 1411 recipients were included (54.4% AA) with 39 521 concentrations utilized to assess intrapatient tacrolimus CV. Overall, intrapatient tacrolimus CV was higher in AAs vs non-AAs (39.9±19.8 % vs. 34.8±15.8% p<0.001). Tacrolimus variability was a significant risk factor for deleterious clinical outcomes. A 10% increase in tacrolimus CV augmented the risk of acute rejection by 20% (aHR 1.20, 1.13–1.28; p<0.001) and the risk of graft loss by 30% (aHR 1.30, 1.23–1.37; p<0.001), with significant effect modification by race for acute rejection, but not graft loss. High tacrolimus variability (CV >40%) was a significant explanatory variable for disparities in AAs; the crude relative risk of acute rejection in AAs was reduced by 46% when including tacrolimus variability in modeling and reduced by 40% for graft loss. Conclusions These data demonstrate that intrapatient tacrolimus variability is strongly associated with acute rejection in AAs and graft loss in all patients. Tacrolimus variability is a significant explanatory variable for disparities in AA recipients.

show abstract

Section: Discussionmentioning

confidence: 99%

Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation

Taber

Fleming

et al. 2017

Transplantation

View full text Add to dashboard Cite

show abstract

“…Oral bioavailability of tacrolimus is poor (25% mean), and is highly variable among individuals (range, 5-90%). [101][102][103] Tacrolimus is able to be absorbed throughout the gastrointestinal tract. 104 The immediate-release formulation is mainly absorbed in the small bowel.…”

Section: Strategies For Managing Nonadherencementioning

confidence: 99%

“…In the plasma, 90% of tacrolimus is bound to proteins. 103 After being metabolized by the liver, the inactive metabolites are bile-excreted. Thus, the intrinsic pharmacokinetic and pharmacodynamic properties of tacrolimus, including erratic absorption, a variable first-pass effect, and unpredictable metabolism, may be responsible for its large intrapatient and inter-subject exposure variability.…”

Section: Strategies For Managing Nonadherencementioning

confidence: 99%

“…This conflicting situation is often seen early after transplantation and leads to inferior outcomes. 103 During pregnancy, the pharmacokinetics properties of CNIs may vary from the nonpregnant state, so drug levels should be closely monitored during pregnancy, with dose adjustment when necessary. 46 Similar considerations may apply during intercurrent illness.…”

Section: Strategies For Managing Nonadherencementioning

confidence: 99%

“…145,146 However, the first-generation protease inhibitors, telaprevir and boceprevir, and the combination ombitasvir/paritaprevir/ritonavir+/−dasabuvir, have a major impact on tacrolimus metabolism, increasing tacrolimus trough concentrations exponentially; therefore, these drugs should be avoided whenever possible. 147,148 The Determinants of IPV of tacrolimus 103,120,121,123,124 Factors Interventions interaction with simeprevir is less strong and tacrolimus dosage modifications should be carried out according to trough concentrations. 149 Additional and updated information may be found at www.hep-druginteractions.org.…”

Section: Highly Modifiable Contributors To Variabilitymentioning

confidence: 99%

See 2 more Smart Citations

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients

et al. 2017

Self Cite

View full text Add to dashboard Cite

Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes. COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant. The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting. 12 Department of Gastroenterology and Hepatology, Erasmus MC, University Hospital Rotterdam, the Netherlands. 13 Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Belgium.14 Abdominal Transplant Surgery, Microbiology and Immunology Department, University Hospitals KU Leuven, Belgium. 15 Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Spain. www.transplantjournal.com S1 S olid organ transplantation has evolved from an experimental procedure to an established treatment option for many types of end-stage organ failure. Both patient and graft outcomes are continuing to improve, and 1-year patient and graft survival currently exceed 80%.1,2 However, survival rates gradually decline over the long term. In kidney transplant, 5-and 10-year graft survival rates in Europe are 77% and 56%, and for liver transplant, 64% and 54% (Figures 1 and 2). 3,4 Although most European countries have seen an increase in both living and deceased donation, transplantation is not available to all who would benefit from the procedure, and there is considerable morbidity and mortality for those listed for transplant.6 Therefore, maximizing long-term graft survival and reducing the need for retransplantation is paramount, not only in improving outcomes for the recipients but also for those awaiting a graft. The improvement in outcomes is predominantly due to reduction in (Transplantation. 2017;101:S1-S41). The authors were approached by Astellas to discuss the practical implementation o...

show abstract

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

Kuypers

2019

Clin Pharma and Therapeutics

136

View full text Add to dashboard Cite

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.

show abstract

Intra-patient variability in tacrolimus exposure: Causes, consequences for clinical management

Cited by 187 publications

References 81 publications

Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation

Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients

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

Contact Info

Product

Resources

About