Pharmacogenetics and Circadian exposure of Tacrolimus and Its Impact on the renal Transplant Outcome: A Way to a Personalized Medicine for Tacrolimus
Shigeru SatohMitsuru SaitoKazuyuki NumakuraYoshio MiuraTakamitsu InoueShinya MaitaTakashi ObaraHiroshi TsurutaShintaro NaritaYohei HorikawaNorihiko TsuchiyaTomonori HabuchiYoko MitobeAtsushi KomatsudaH.‐Matsuo KagayaMasatomo Miura
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Tacrolimus gained FDA approval for use in liver transplantation in 1994 and, approximately 3 years later, was approved for the prevention of acute rejection in kidney transplantation. Over the last decade tacrolimus has become the calcineurin inhibitor of choice for the prevention of rejection in renal transplantation. The objective of this study was to provide a review and update of the literature on the use of tacrolimus in renal transplantation. Numerous clinical trials have shown tacrolimus to be superior to cyclosporine in the prevention of acute rejection and recent trials have demonstrated superiority of tacrolimus over cyclosporine in terms of allograft survival. Post-transplant diabetes remains more common with tacrolimus than cyclosporine, despite lower doses of both tacrolimus and corticosteroids. A novel once-daily dosage form of tacrolimus has recently been developed and is approved for use in Europe. Tacrolimus remains an important immunosuppressant for the prevention of acute rejection. The prolonged-release formulation may improve compliance and possibly long-term outcomes.
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Introduction: Tacrolimus-based immunosuppression remains the immunosuppressive drug of choice in kidney transplantation.Areas covered: Its safety profile is closely linked to its pharmacokinetic properties. A narrow therapeutic range allows to limit under- and over-immunosuppression consequences. Minimization of tacrolimus exposure, using appropriate companion drugs, leads to the best renal outcomes in the long term. Also, reducing tacrolimus exposure variability helps in reducing tacrolimus toxicity. The novel concept of tacrolimus concentration-to-dose ratio (C/D ratio) associates with renal outcomes as well and provides some new possible improvements on tacrolimus safety, possibly by identifying kidney transplant recipient subpopulations at higher risk of tacrolimus toxicity. Similarly, the incidence of new-onset diabetes after transplantation (NODAT), a major side-effect of tacrolimus, can also be reduced by optimizing tacrolimus exposure. In this review, the authors summarize the safety profile of tacrolimus when optimizing mean tacrolimus exposure, tacrolimus exposure variability and tacrolimus C/D ratio. The impact of these adjustments on nephrotoxicity and NODAT is reviewed. Using such prescription optimization, tacrolimus' safety profile is positive.Expert opinion: Tacrolimus-based immunosuppression remains a valid option for kidney transplant recipients, and might even improve by individualizing prescriptions, the next frontier in transplant immunosuppression.
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Introduction Diltiazem (DTZ) is used as a tacrolimus (FK)-sparing agent for kidney transplant recipients (KTRs). Considerable inter-patient variability in DTZ’s FK sparing effect has been observed, which may be partly explained by pharmacogenetics differences. Objectives The primary objective was to evaluate the dose sparing effect of DTZ on FK in relation to CYP3A4, CYP3A5 and MDR-1 genotypes in KTRs. Methods This was a single–center, retrospective study conducted at Singapore General Hospital. KTRs aged between 18 and 75 years who received FK with or without DTZ between January 2000 to December 2016 were recruited. Blood samples were collected to analyse for CYP3A4, CYP3A5 and MDR-1 genotypes. KTRs’ transplant-related information, FK drug levels and doses for FK and DTZ were collected. Results Seventy two KTRs were recruited, of which 42 (58.3%) were on DTZ. For KTRs who were CYP3A5 non-expressers (*3/*3), the median concentration-to-dose ratio (C0/Dose) was significantly higher for KTRs on DTZ [DTZ(+)] compared to KTRs not on DTZ [DTZ(–)] (159.7 vs. 126.8 ng/mL per mg/kg/day; p= 0.047). For KTRs with more than three mutant copies of MDR-1 (1236C>T, 3435C>T and 2677G>T) polymorphisms, the median C0/Dose was significantly higher for DTZ(+) compared to DTZ(–) group (150.9 vs. 81.1 ng/mL per mg/kg/day; p= 0.045). Conclusion KTRs who were CYP3A5 and MDR-1 non-expressers potentially benefit from the addition of DTZ. This suggests the potential use of CYP3A5 and MDR-1 genotyping to guide FK-DTZ combination in KTRs.
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You have accessJournal of UrologyPodium 50, Wednesday, May 23, 2007 10:00 am - 12:00 pm1 Apr 20071815: Tacrolimus Circadian Pharmacokinetics and Pharmacogenetics in the Maintenance Stage after Renal Transplantation and the Implications of Chronic Allograft Nephropathy Shigeru Satoh, Mitsuru Saito, Takamitsu Inoue, Kazuyuki Numakura, Norihiko Tsuchiya, Hideaki Kagaya, Masatomo Miura, Kazuyuki Inoue, Toshio Suzuki, and Tomonori Habuchi Shigeru SatohShigeru Satoh More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , Hideaki KagayaHideaki Kagaya More articles by this author , Masatomo MiuraMasatomo Miura More articles by this author , Kazuyuki InoueKazuyuki Inoue More articles by this author , Toshio SuzukiToshio Suzuki More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)32002-0AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "1815: Tacrolimus Circadian Pharmacokinetics and Pharmacogenetics in the Maintenance Stage after Renal Transplantation and the Implications of Chronic Allograft Nephropathy." The Journal of Urology, 177(4S), pp. 603–604 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 177Issue 4SApril 2007Page: 603-604 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Shigeru Satoh More articles by this author Mitsuru Saito More articles by this author Takamitsu Inoue More articles by this author Kazuyuki Numakura More articles by this author Norihiko Tsuchiya More articles by this author Hideaki Kagaya More articles by this author Masatomo Miura More articles by this author Kazuyuki Inoue More articles by this author Toshio Suzuki More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement PDF downloadLoading ...
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Pretransplantation adaptation of the daily dose of tacrolimus to CYP3A5 genotype is associated with improved achievement of target trough concentration (C0 ), but whether this improvement affects clinical outcomes is unknown. In the present study, we have evaluated the long-term clinical impact of the adaptation of initial tacrolimus dosing according to CYP3A5 genotype: The transplantation outcomes of the 236 kidney transplant recipients included in the Tactique study were retrospectively investigated over a period of more than 5 years. In the Tactique study, patients were randomly assigned to receive tacrolimus at either a fixed dosage or a dosage determined by their genotype, and the primary efficacy end point was the proportion of patients for whom tacrolimus C0 was within target range (10-15 ng/mL) at day 10. Our results indicate that the incidence of biopsy-proven acute rejection and graft survival were similar between the control and the adapted tacrolimus dose groups, as well as between the patients who achieve the tacrolimus C0 target ranges earlier. Patients' death, cancer, cardiovascular events, and infections were also similar, and renal function did not change. We conclude that optimization of initial tacrolimus dose using pharmacogenetic testing does not improve clinical outcomes.
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Tacrolimus,a novel macrocyclic lactone with potent immunosuppressive properties,is generally used in organ transplantation to prevent allograft rejection.There is a wide interindividual variation in pharmacokinetics and therapeutic window of tacrolimus in liver transplant recipients.Recently,many studies indicated that there is a close association between interindividual variation of tacrolimus and genetic polymorphism of CYP3A5 and MDR1.In this review,pharmacodynamics,pharmacokinetics,therapeutic window and pharmacogenomics of tacrolimus in liver transplantation are discussed.
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Barbarino, Julia M.; Staatz, Christine E.; Venkataramanan, Raman; Klein, Teri E.; Altman, Russ B. Author Information
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Tacrolimus is the gold standard immunosuppressant administered in solid organ and stem cell transplantation to avoid graft rejection post-transplant. Despite its widespread use, there is a large variation in response to therapy, likely due to high inter-individual pharmacokinetic variability. Therapeutic drug monitoring is employed to improve clinical response and reduce toxicity. There is substantial evidence that pharmacogenetics influences drug exposure and response. CYP3A5 genotype significantly impacts oral tacrolimus concentrations and response after solid organ transplantation. There are fewer studies in stem cell transplantation and with intravenous tacrolimus dosing. This report highlights recent evidence suggesting genes such as CYP3A4 and ABCB1 play a larger role after intravenous dosing compared with CYP3A5, and the role for novel genes on tacrolimus outcomes.
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