Impact of Tacrolimus Intraindividual Variability and CYP3A5 Genetic Polymorphism on Acute Rejection in Kidney Transplantation

Ro, Han; Min, Sang Il; Yang, Jaeseok; Moon, Kyung Chul; Kim, Yon Su; Kim, Sang Joon; Ahn, Curie; Ha, Jongwon

doi:10.1097/ftd.0b013e3182731809

Cited by 62 publications

(119 citation statements)

References 24 publications

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“…A high intraindividual pharmacokinetic variability of tacrolimus has been associated with a poor long-term transplant outcome (17,25). This study shows that IIV of dosenormalized C min in pediatric patients is significantly higher for Tac-OD compared with Tac-BID (21.4 AE 7.6% vs. 16.5 AE 10.2%, p ¼ 0.033).…”

Section: Once-daily Tacrolimus In Pediatric Patientsmentioning

confidence: 56%

See 1 more Smart Citation

Conversion of Twice-Daily Tacrolimus to Once-Daily Tacrolimus Formulation in Stable Pediatric Kidney Transplant Recipients: Pharmacokinetics and Efficacy

Min

Kang

et al. 2013

American Journal of Transplantation

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The pharmacokinetics, efficacy and safety of once-daily tacrolimus formulation (Tac-OD) were assessed in 34 stable pediatric kidney transplant recipients. Enrolled patients received their dose of twice-daily tacrolimus formulation (Tac-BID) on study Days 0 through 7. On the morning of study Day 8, the total daily doses for patients were converted to Tac-OD on a 1:1 basis and maintained on a once-daily morning dosing regimen. Tacrolimus pharmacokinetic profiles were obtained on study Days 7, 14 and 28 (after dose adjustment). Although the mean C 0 concentrations (4.10 AE 1.16-3.53 AE 1.10 ng/mL, p ¼ 0.004), and AUC 0-24 (151.8 AE 41.6-129.8 AE 39.3 ng h/mL, p < 0.001) were decreased significantly after a 1:1 based conversion, there was high interindividual variability. The dose of Tac-OD was decreased in 26.5% and increased in 44.1% of patients. The resultant tacrolimus dose and pharmacokinetic profiles on study Day 28 were comparable to those on Day 7. There were no serious adverse events. In conclusion, Tac-BID can be safely converted to Tac-OD in stable pediatric kidney transplant patients with the heightened therapeutic drug monitoring. Effects of drug conversion on the cardiovascular risk factors, neurological side effects and adherence should be further evaluated.

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Section: Once-daily Tacrolimus In Pediatric Patientsmentioning

confidence: 56%

“…Intra-individual variability (IIV) of tacrolimus levels was also compared (17). For calculation and comparison of IIV between two formulations, the results of the tacrolimus-level measurement between 6 months prior to drug switching and 6 months after drug switching were included.…”

Section: End Pointsmentioning

confidence: 99%

Conversion of Twice-Daily Tacrolimus to Once-Daily Tacrolimus Formulation in Stable Pediatric Kidney Transplant Recipients: Pharmacokinetics and Efficacy

Min

Kang

et al. 2013

American Journal of Transplantation

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“…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%

“…8, 27 The impact of CYP 3A5 on tacrolimus variability is not fully elucidated, with both positive and negative associations in the literature. 11, 33–35 However, given the limitations of these studies, including small sample-size and limited information on race, the true impact of CYP 3A5 polymorphisms of tacrolimus trough variability has yet to be determined. 13 It is important to note that we did not assess the correlation between CYP 3A5 genotype, tacrolimus variability and outcomes in this study; thus, future studies assessing genotype and its impact on tacrolimus variability and clinical outcomes, particularly within AA recipients, are needed.…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation

Taber

Fleming

et al. 2017

Transplantation

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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.

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“…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]. A high Tac IPV was also associated with more acute rejection after kidney transplantation [49]. Recently, Sapir-Pichhadze et al observed that a higher Tac IPV was associated with more late allograft rejection, transplant glomerulopathy, graft loss, and death with a functioning transplant [50].…”

Section: Intrapatient Variabilitymentioning

confidence: 98%

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

Andrews

Winter

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

105

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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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Impact of Tacrolimus Intraindividual Variability and CYP3A5 Genetic Polymorphism on Acute Rejection in Kidney Transplantation

Abstract: The IIV of tacrolimus trough concentrations had a significant impact on rejection-free survival. The effect was influenced by CYP3A5 polymorphism, although the tacrolimus variability itself was not determined by the CYP3A5 polymorphism.

Cited by 62 publications

References 24 publications

Conversion of Twice-Daily Tacrolimus to Once-Daily Tacrolimus Formulation in Stable Pediatric Kidney Transplant Recipients: Pharmacokinetics and Efficacy

Conversion of Twice-Daily Tacrolimus to Once-Daily Tacrolimus Formulation in Stable Pediatric Kidney Transplant Recipients: Pharmacokinetics and Efficacy

Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation

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

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