Tacrolimus Pharmacokinetics of Once- Versus Twice-Daily Formulations in De Novo Kidney Transplantation

Włodarczyk, Zbigniew; Ostrowski, Marek; Mourad, Michel; Krämer, Bernhard K.; Abramowicz, Daniel; Oppenheimer, Federico; Miller, Derek M.; Dickinson, James; Undre, Nasrullah

doi:10.1097/ftd.0b013e31824d1620

Cited by 32 publications

(35 citation statements)

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“…Similar to other reports [9][10][11][12][13] , the present study also showed that there was a good correlation between AUC 0-24 and C 24 for both IR and MR tacrolimus. The fact that the slope of the line best fit was similar for both formulations indicates that the same therapeutic drug monitoring for IR tacrolimus could be applied to MR tacrolimus.…”

Section: Discussionsupporting

confidence: 81%

“…Before our study, a set of clinical trials had been conducted to compare the PK profi les of tacrolimus between IR and MR formulations [9][10][11][12][13] . The clinical trial in de novo liver transplant patients showed that the systemic exposure AUC 0-24 on d 1 was approximately 50% lower for MR tacrolimus than for IR tacrolimus at equivalent doses, whereas values at steady state (d 14 and w 6) were similar for both formulations [13] .…”

Section: Discussionmentioning

confidence: 99%

“…This formulation, known commercially as Advagraf, has been approved in more than 30 countries and regions as of 2010. The pharmacokinetics (PK) of tacrolimus have been compared between MR and IR formulations in stable kidney, liver, and heart transplant patients, and in de novo kidney and liver transplant recipients [9][10][11][12][13] . However, there is few clinical data on Chinese patients.…”

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confidence: 99%

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Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients

et al. 2011

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npg IntroductionTacrolimus is an immunosuppressive agent that inhibits cellular and T-cell-dependent humoral responses via the inactivation of the intracellular calcineurin complex. It has been marketed mainly for preventing or treating graft rejection in solid organ transplantation [1,2] . Tacrolimus has a narrow therapeutic window, and its bioavailability shows high interand intra-individual variability [1,3,4] . The systemic exposure AUC is a significant efficacy variable; therefore, therapy is optimized on an individual patient basis by monitoring trough levels as surrogate markers of exposure. In clinical practice, the current immediate release (IR) tacrolimus is administered twice a day, once in the morning and once in the evening, to maintain whole blood trough concentrations generally within the range of 5-15 μg/L to prevent rejection. Tacrolimus should be taken 1 h before or at least 2 to 3 h after a meal to prevent a food effect. This schedule may be an additional burden for the patient, especially for the evening dose, because it may interfere with daily activities. Transplant recipients often receive an immunosuppressive regimen consisting of multiple medications; thus, a formulation that can be taken once daily is considered to be beneficial to patients. A new oral modifi ed release (MR) formulation of tacrolimus has been developed to allow a once-daily dosing regimen. Clinical studies demonstrate that MR tacrolimus is as effi cient and safe as IR tacrolimus [5][6][7][8] . This formulation, known commercially as Advagraf, has been approved in more than 30 countries and regions as of 2010. The pharmacokinetics (PK) of tacrolimus have been compared between MR and IR formulations in stable kidney, liver, and heart transplant patients, and in de novo kidney and liver transplant recipients [9][10][11][12][13] . However, there is few clinical data on Chinese patients. The present study was Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients Aim: To evaluate the pharmacokinetics of tacrolimus in Chinese stable liver transplant recipients converted from immediate release (IR) tacrolimus-based immunosuppression to modifi ed release (MR) tacrolimus-based immunosuppression. Methods: Open-label, multi-center study with a one-way conversion design was conducted. Eighty-three stable liver recipients (6-24 months post-transplant) with normal renal and stable hepatic function were converted from IR tacrolimus twice-daily treatment to MR tacrolimus once-daily treatment on a 1:1 (mg:mg) total daily dose basis. Twenty-four hour pharmacokinetic studies were carried out on d 0 (pre-conversion), d 1, and d 84 (post-conversion). Results: The area under the blood concentration-time curve of MR tacrolimus from 0 to 24 h (AUC 0-24 ) on d 1 was comparable to that of IR tacrolimus on d 0, with a 90% confi dence interval (CI) for MR/IR tacrolimus of 92%-97%. The AUC 0-24 value for MR tacrolimus on d 84 with the daily dose increased by 14% ...

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients

et al. 2011

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“…Increasing pill burden is associated with decreased adherence [20,21], and lack of adherence is associated with acute rejection [22,23] and graft loss [21,[24][25][26]. While there are currently available prolonged-release tacrolimus hard capsule formulations designed for once-daily dosing, data from these formulations do not suggest that they offer improved bioavailability over tacrolimus twice-daily capsules [27][28][29]. In a clinical trial in de novo kidney transplant recipients, another once-daily formulation already available on the market (Advagraf Ò in Europe; Astagraf XL Ò in the US) failed to demonstrate a reduction in peak concentration in comparison with the twice-daily formulation [30].…”

Section: Overview Of the Marketmentioning

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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“…Међутим, у раније урађеној шестонедељ-ној студији код пацијената којима је транс-плантиран бубрег вршено је такође поређење фармакокинетских параметара лека након примене исте дозе такролимуса (0,2 mg/kg/ дан), без обзира на формулацију 23 . Резултати су показали да је AUC0-24 за око 30% мањи код групе са такролимусом са продуженим ослобађањем након првог дана примене лека, док се та разлика губи током 14. пост-транс-плантацијског дана и 6 недеља након тога.…”

Section: 25unclassified

Comparative pharmacokinetic characteristics of tacrolimus following application of its different pharmaceutical formulations in humans

Rančić¹,

Dragojevic-Simic²

2017

Racion ter

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САЖЕТАКТакролимус је имуносупресивни лек који представља камен темељац у превенцији од-бацивања графта после трансплантације со-лидних органа. Након дугогодишње употребе фармацеутске формулације овог лека која се примењује два пута дневно, уследила је нова ера примене такролимуса са продуженим ос-лобађањем, који се примењује једном дневно. Циљ овог кратког литературног приказа је да се сагледају упоредо фармакокинетске карак-теристике овог лека након његове примене у облику капсула два пута на дан, на 12 сати, и фармацеутске формулације са продуженим ослобађањем, која се дозира једном дневно у здравих особа и пацијената. Међутим, тек бу-дуће клиничке студије ће показати да ли су ове две формулације заиста упоредиве што се тиче фармакокинетских параметара, и, што је још важније, у смислу дуготрајне безбедности такролимуса са продуженим ослобађањем, преживљавања графта и пацијената.Кључне речи: такролимус, фармакокине-тика, трансплантација, фармацеутска форму-лација. ABSTRACTTakrolimus is a cornerstone immunosuppressant in the prevention of solid organ rejection following transplantation. After long-term use of twice daily tacrolimus, a new era of application of extended release tacrolimus for once-daily dosing ensued. The aim of this short communication was to compare pharmacokinetic characteristics of tacrolimus following its application as twice daily drug capsules, each 12 hours, and once-daily capsules with extended release in healthy people and patients. However, only future clinical trials would show whether these two drug formulations are really comparable as far as pharmacokinetic parameters are concerned, and, what is more important, taking into account longterm safety of extended release tacrolimus, survival of grafts and patients themselves.

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Tacrolimus Pharmacokinetics of Once- Versus Twice-Daily Formulations in De Novo Kidney Transplantation

Abstract: These results suggest that initiating tacrolimus therapy before transplant reduces the difference in exposure between Tacrolimus QD and Tacrolimus BID.

Cited by 32 publications

References 11 publications

Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients

Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients

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

Comparative pharmacokinetic characteristics of tacrolimus following application of its different pharmaceutical formulations in humans

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