Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients

Santeusanio, Andrew; Mathis, Erin; Notarbartolo, Monica; Labbozzetta, Manuela; Poma, Paola; Provenzani, A; Polidori, Carlo; Vizzini, Giovanni; Polidori, Piera; D’Alessandro, Natale

doi:10.3748/wjg.v19.i48.9156

Cited by 87 publications

(94 citation statements)

References 115 publications

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“…Although rapidly absorbed in the GI tract, the bioavailability of tacrolimus from the traditional twice-daily capsule formulation is low and variable, ranging from 17 to 23% [7]. The relatively low bioavailability of tacrolimus is believed to be due to a number of factors including poor water solubility, extensive first pass metabolism, p-glycoprotein-mediated efflux and the ingestion of food [15]. Tacrolimus twice-daily capsules are associated with a characteristic high peak (C max ) following dosing, which may be associated with increased toxicity [16][17][18].…”

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confidence: 99%

Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations

Grinyó

Petruzzelli

2014

Expert Review of Clinical Immunology

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Tacrolimus is a cornerstone of the immunosuppression regimen for prevention of allograft rejection in kidney and liver transplantations, with efficacy proven in many clinical trials. The currently available and extensively used tacrolimus formulations are flawed by large inter-and intra-individual variability, low bioavailability, wide peak-to-trough fluctuations and a narrow therapeutic index. Drug delivery technology can significantly impact the pharmacologic action of a drug, influencing its pharmacokinetic and subsequent therapeutic profile. LCP-Tacro is a novel, prolonged-release, MeltDose Ò formulation of tacrolimus designed for once-daily administration. A hallmark differentiation between this formulation and other once-and twice-daily tacrolimus products is the proprietary MeltDose drug delivery technology which is designed to improve the bioavailability of drugs with low water solubility. Considering the studies conducted to date, once-daily LCP-Tacro has shown improved pharmacokinetic properties, rapid achievement of therapeutic trough levels, consistent exposure, non-inferior efficacy and similar safety, with lower tacrolimus dose than other tacrolimus formulations. World-wide there were an estimated 77,800 kidney transplants performed in 2012 (69% of all transplants) and 23,986 liver transplants (21% of all transplants) [1]. Data from the US show that, in 2013 more than half of the 28,953 transplants performed were kidney transplants (58.3%, n = 16,894) [2]; liver transplants were the next most frequent, comprising 22.2% (n = 6455) of all US transplants [2]. The number of individuals in need of organ transplantation outweighs the availability of organs -as of June 2014; data from the Organ Procurement and Transplantation Network showed that 100,967 individuals were on the waitlist for a kidney transplant and 15,758 individuals were on the waitlist for a liver transplant [3]. For individuals who receive a transplant, lifelong administration of immunosuppressive medications are required to prevent organ rejection. The arsenal of immunosuppressive drugs has evolved greatly since the beginnings of successful organ transplantation. A combination of azathioprine and corticosteroids was the original mainstay regimen in the early period of organ transplantation. A major advance in immunosuppression for prevention of allograft rejection came in the late 1970's with the advent of the calcineurin inhibitor (CNI) cyclosporine A [4][5][6]. The 'cyclosporine era' of the 1980's saw greatly improved short-and mid-term graft survival following transplantation. Immunosuppressive drugs have continued to evolve and the availability of improved drugs and regimens has contributed largely to the current high short-and long-term survival rates (survival following living donor transplant, 1-year kidney: 98%; 5-year kidney: 90%; 1-year liver: 90%; 5-year liver: 77%) [2]. In 1994, the EMA approved another CNI, tacrolimus, , Astellas Pharma US, Inc.), for the prophylaxis of organ rejection in kidney, liver and heart transplant ...

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confidence: 99%

Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations

Grinyó

Petruzzelli

2014

Expert Review of Clinical Immunology

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“…Nevertheless, transplant recipient pharmacogenomics could account in part for the high alphatorquevirus levels observed at the 2‐week time point among non‐white respondents in the current study: Genetic polymorphisms (eg, CYP3A4) that have a characteristic race‐specific distribution and which may impact tacrolimus metabolism were previously described . Moreover, in a study of the Cylex Immune Cell Function assay (a functional test of immune status occasionally used in lung transplant recipients), African Americans had lower immune function measures at all post‐transplant time points as compared to non‐African Americans .…”

Section: Discussionmentioning

confidence: 80%

Anellovirus loads are associated with outcomes in pediatric lung transplantation

Blatter

Sweet

Conrad

et al. 2017

Pediatric Transplantation

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Anelloviruses are DNA viruses ubiquitously present in human blood. Due to their elevated levels in immunosuppressed patients, anellovirus levels have been proposed as a marker of immune status. We hypothesized that low anellovirus levels, reflecting relative immunocompetence, would be associated with adverse outcomes in pediatric lung transplantation. We assayed blood samples from 57 patients in a multicenter study for alpha- and betatorquevirus, two anellovirus genera. The primary short-term outcome of interest was acute rejection, and longer-term outcomes were analyzed individually and as "composite" (death, chronic rejection, or retransplant within 2 years). Patients with low alphatorquevirus levels at 2 weeks post-transplantation were more likely to develop acute rejection within 3 months after transplant (P = .013). Low betatorquevirus levels at 6 weeks and 6 months after transplant were associated with death (P = .047) and the composite outcome (P = .017), respectively. There was an association between low anellovirus levels and adverse outcomes in pediatric lung transplantation. Alphatorquevirus levels were associated with short-term outcomes (ie, acute rejection), while betatorquevirus levels were associated with longer-term outcomes (ie, death, or composite outcome within 2 years). These observations suggest that anelloviruses may serve as useful biomarkers of immune status and predictors of adverse outcomes.

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“…In addition, genome-wide association studies revealed different genetic susceptibility loci for SLE between ethnicity groups 45. Also, the CYP3A5 polymorphism determines the metabolism of TAC, and a lower bioavailability of TAC in African-American kidney transplant recipients46 47 is well described. Altogether emphasising that the extrapolation of these data to other ethnic groups is not self-evident.…”

Section: Discussionmentioning

confidence: 99%

TAC-TIC use of tacrolimus-based regimens in lupus nephritis

et al. 2016

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Current guidelines do not mention tacrolimus (TAC) as a treatment option and no consensus has been reported on the role of TAC in lupus nephritis (LN). The present study aimed to guide clinical judgement on the use of TAC in patients with LN. A meta-analysis was performed for clinical studies investigating TAC regimens in LN on the basis of treatment target (induction or maintenance), concomitant immunosuppression and quality of the data. 23 clinical studies performed in patients with LN were identified: 6 case series, 9 cohort studies, 2 case-control studies and 6 randomised controlled trials (RCTs). Of the 6 RCTs, 5 RCTs investigated TAC regimens as induction treatment and 1 RCT as maintenance treatment. Five RCTs investigated TAC in combination with steroids and 2 TAC with mycophenolate plus steroids. All RCTs were performed in patients of Asian ethnicity. In a meta-analysis, TAC regimens achieved a significantly higher total response (relative risk (RR) 1.23, 95% CI 1.12 to 1.34, p<0.05) and significantly higher complete response (RR 1.48, 95% CI 1.23 to 1.77, p<0.05). The positive outcome was predominantly defined by the largest RCT investigating TAC with mycophenolate plus steroids. Regarding safety, the occurrence of leucopoenia was significantly lower, while the occurrence of increased creatine was higher. Clinical studies on TAC regimens for LN are limited to patients of Asian ethnicity and hampered by significant heterogeneity. The positive results on clinical efficacy of TAC as induction treatment in LN cannot be extrapolated beyond Asian patients with LN. Therefore, further confirmation in multiethnic, randomised trials is mandatory. Until then, TAC can be considered in selected patients with LN.

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Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients

Cited by 87 publications

References 115 publications

Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations

Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations

Anellovirus loads are associated with outcomes in pediatric lung transplantation

TAC-TIC use of tacrolimus-based regimens in lupus nephritis

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