Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of <i>de novo</i> anti-HLA donor-specific antibodies in kidney transplant recipients

Rojas, Aleixandra Mendoza; Hesselink, Dennis A.; Besouw, Nicole M. van; Baan, Carla C.; Gelder, Teun van

doi:10.1080/1744666x.2020.1693263

Cited by 27 publications

(15 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ten years ago Borra et al demonstrated that patients with high intra-patient variability more often reached a composite endpoint consisting of graft loss, biopsy-proven chronic allograft nephropathy, and 'doubling in plasma creatinine concentration in the period between t = 12 months post-transplantation and last follow-up' (Borra et al, 2010). A high intra-patient variability in tacrolimus exposure is now recognized as a predictor of poor clinical outcome (van Gelder, 2014;Mendoza Rojas et al, 2019). Rodrigo et al found that a higher intra-patient variability was independently related to development of donor-specific antibodies and graft-loss (Rodrigo et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients

et al. 2020

Self Cite

View full text Add to dashboard Cite

Tacrolimus is metabolized by CYP3A4 and CYP3A5 enzymes. Patients expressing CYP3A5 (in Caucasian patients about 15% of the population but more frequent in African Americans and Asians) have a dose requirement that is around 50% higher than non-expressers to reach the target concentration. CYP3A5 expressers can be considered fast metabolizers. The trough concentration/dose (C 0 /D) ratio of tacrolimus has recently been proposed as a prognostic marker for poor outcome after kidney transplantation. Patients with a low C 0 /D ratio (also referred to as fast metabolizers) seem to have more tacrolimus-related nephrotoxicity, more BK-viremia, and a lower graft survival. At first sight, the expression of CYP3A5 and a low C 0 /D ratio seem to be overlapping factors, both pointing towards patients in whom a higher tacrolimus dose is needed to reach the tacrolimus target concentration. However, there are important differences, and these differences may explain why the impact of the C 0 /D ratio on long term outcome is stronger than for CYP3A5 genotype status. Patients with a low C 0 /D ratio require a high tacrolimus dose and are exposed to high tacrolimus peak concentrations. The higher peak exposure to tacrolimus (and/or its metabolites) may explain the higher incidence of nephrotoxicity, BK-viremia and graft loss. A potential confounder is the concurrent maintenance treatment of corticosteroids, as steroids are sometimes continued in patients at high immunological risk. Steroids induce the metabolism of tacrolimus via pregnane X receptor mediated increased CYP3A4 expression, resulting in lower tacrolimus C 0 /D ratio in high risk patients. Also non-adherence may result in lower C 0 /D ratio which is also associated with poor outcome. The C 0 /D ratio of tacrolimus does seem to identify a group of patients with increased risk of poor outcome after kidney transplantation. Our recommendation is to monitor tacrolimus peak concentrations in these patients, and if these are high then target slightly lower pre-dose concentrations. Another possibility would be to switch to a prolonged release formulation or to dose the drug more frequently, in smaller doses, to avoid high peak concentrations.

show abstract

Section: Introductionmentioning

confidence: 99%

The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, therapeutic monitoring is required to ensure patients receive optimal exposure to the drug. Supratherapeutic tacrolimus concentrations may increase the risk of nephrotoxicity while subtherapeutic concentrations may increase the risk of antibody-mediated organ rejection over time (Sikma et al, 2015;Mendoza Rojas et al, 2019). Drug concentrations may also be altered by drug-induced PK changes.…”

Section: Pk/pd Variabilitymentioning

confidence: 99%

Precision Dosing Priority Criteria: Drug, Disease, and Patient Population Variables

et al. 2020

View full text Add to dashboard Cite

The administered dose of a drug modulates whether patients will experience optimal effectiveness, toxicity including death, or no effect at all. Dosing is particularly important for diseases and/or drugs where the drug can decrease severe morbidity or prolong life. Likewise, dosing is important where the drug can cause death or severe morbidity. Since we believe there are many examples where more precise dosing could benefit patients, it is worthwhile to consider how to prioritize drug-disease targets. One key consideration is the quality of information available from which more precise dosing recommendations can be constructed. When a new more precise dosing scheme is created and differs significantly from the approved label, it is important to consider the level of proof necessary to either change the label and/or change clinical practice. The cost and effort needed to provide this proof should also be considered in prioritizing drug-disease precision dosing targets. Although precision dosing is being promoted and has great promise, it is underutilized in many drugs and disease states. Therefore, we believe it is important to consider how more precise dosing is going to be delivered to high priority patients in a timely manner. If better dosing schemes do not change clinical practice resulting in better patient outcomes, then what is the use? This review paper discusses variables to consider when prioritizing precision dosing candidates while highlighting key examples of precision dosing that have been successfully used to improve patient care.

show abstract

“…Therapeutic drug monitoring (TDM) is essential for achieving therapeutic trough concentrations. Despite the fact that monitoring blood trough concentrations is an effective method for adjusting tacrolimus oral doses, clinical studies have reported that it may not be valuable for future dosage estimation and may also not be an accurate assessment of overall drug exposure among various individuals [ 17 , 23 , 24 , 25 , 26 ]. It is sometimes challenging to achieve and maintain target tacrolimus trough concentrations despite periodic tacrolimus TDM [ 3 ].…”

Section: Intra-individual and Inter-individual Tacrolimus Pk Variamentioning

confidence: 99%

“…As discussed earlier, tacrolimus has a narrow therapeutic index and substantial inter-individual PK variability with standard weight-based dosing [ 56 , 57 ]. Moreover, tacrolimus also has a high intra-individual variability (IPV), resulting in sub-therapeutic and supra-therapeutic concentrations despite comparable dosing [ 25 ]. The coefficient of variation (CV) serves as a well-established biomarker of adherence in pediatric and adult groups of kidney transplant recipients [ 58 ].…”

Section: Intra-individual and Inter-individual Tacrolimus Pk Variamentioning

confidence: 99%

See 1 more Smart Citation

Impacts of High Intra- and Inter-Individual Variability in Tacrolimus Pharmacokinetics and Fast Tacrolimus Metabolism on Outcomes of Solid Organ Transplant Recipients

Hansrivijit

Kovvuru

Kanduri

et al. 2020

JCM

View full text Add to dashboard Cite

Tacrolimus is a first-line calcineurin inhibitor (CNI) and an integral part of the immunosuppressive strategy in solid organ transplantation. Being a dose-critical drug, tacrolimus has a narrow therapeutic index that necessitates periodic monitoring to maintain the drug’s efficacy and reduce the consequences of overexposure. Tacrolimus is characterized by substantial intra- and inter-individual pharmacokinetic variability. At steady state, the tacrolimus blood concentration to daily dose ratio (C/D ratio) has been described as a surrogate for the estimation of the individual metabolism rate, where a low C/D ratio reflects a higher rate of metabolism. Fast tacrolimus metabolism (low C/D ratio) is associated with the risk of poor outcomes after transplantation, including reduced allograft function and survival, higher allograft rejection, CNI nephrotoxicity, a faster decline in kidney function, reduced death-censored graft survival (DCGS), post-transplant lymphoproliferative disorders, dyslipidemia, hypertension, and cardiovascular events. In this article, we discuss the potential role of the C/D ratio in a noninvasive monitoring strategy for identifying patients at risk for potential adverse events post-transplant.

show abstract

Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of de novo anti-HLA donor-specific antibodies in kidney transplant recipients

Abstract: van Gelder (2019) Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of denovo anti-HLA donor-specific antibodies in kidney transplant recipients,

Cited by 27 publications

References 89 publications

The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients

The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients

Precision Dosing Priority Criteria: Drug, Disease, and Patient Population Variables

Impacts of High Intra- and Inter-Individual Variability in Tacrolimus Pharmacokinetics and Fast Tacrolimus Metabolism on Outcomes of Solid Organ Transplant Recipients

Contact Info

Product

Resources

About