Pharmacokinetics in stable heart transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations

Alloway, Rita R.; Vanhaecke, Johan; Yonan, Nizar; White, Michel; Haddad, Haissam; Rábago, Gregorio; Tymchak, Wayne; Díaz‐Molina, Beatriz; Grimm, Michael; Eiskjær, Hans; Karpf, Carmen; Undre, Nasrullah

doi:10.1016/j.healun.2011.02.008

Cited by 25 publications

(25 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: 92%

“…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.…”

Section: Introductionmentioning

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: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Међутим, показано је да 50% паци-јената након конверзије захтева промену дозе у смислу повећања или смањења оне која је иницијална након конверзије [25][26][27][28][29][30][31] . Због тога, тренутно су у току клиничке студије у којима је иницијална доза при конверзији 70% од дозе пре конверзије 32 .…”

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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“…6 However, clinical evidence from liver, kidney, and heart transplant recipients during clinical trials indicated that there were no marked differences between the efficacy and safety profiles of the 2 formulations. [7][8][9] The pharmacokinetics characteristics of once-daily tacrolimus in livingdonor liver transplant (LDLT) recipients have not yet been assessed; therefore, the objective of this study was to examine the pharmacokinetics properties of once-daily tacrolimus, both after the first oral dose and under steady-state conditions (before the 10th oral dose), in patients undergoing de novo LDLT.…”

Section: Introductionmentioning

confidence: 99%

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Song

Lee²,

Hwang³

et al. 2016

Exp Clin Transplant

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Objectives: Sustained-release once-daily tacrolimus pharmacokinetics have not yet been characterized in de novo living-donor liver transplant recipients. Here, a 12-week, phase IV, single center, open-label, prospective pilot study was conducted to investigate the pharmacokinetics of this formulation in these patients. Materials and Methods: Patients received continuous intravenous infusion of tacrolimus on days 0 to 5 after transplant, which was followed by oral once-daily sustained-release tacrolimus. Two 24-hour pharmacokinetics profiles were generated for 10 patients on days 6 and 14. Secondary endpoints were minimum (trough level) and maximum whole blood concentrations, time to maximum concentration, and incidences of acute rejection, patient and graft survival, and adverse events. Results: Mean doses (± standard deviation) of sustained-release tacrolimus on days 6 and 14 were 0.14 ± 0.03 and 0.17 ± 0.04 mg/kg. Levels were within the recommended range throughout the study. When the actual dose was examined, area under the curve from 0 to 24 hours on day 14 was 1.8-fold higher than that on day 6 (423.9 vs 235.7 ng × h/mL). When tacrolimus was normalized to 0.1 mg/kg, area under the curve from 0 to 24 hours on day 14 was 1.5-fold higher than on day 6 (279.3 vs 183.4 ng × h/mL). When we used the actual dose, we found the correlation coefficient between area under the curve from 0 to 24 hours and trough level to be higher on day 6 (r = 0.87) than on day 14 (r = 0.691). No acute rejections, graft losses, patient deaths, or drug-related adverse events were reported. Conclusions: Initial intravenous followed by sustainedrelease tacrolimus was safe and efficacious in livingdonor liver transplant recipients. The mean area under the curve from 0 to 24 hours on day 14 was higher than previously reported; this difference may reflect cautious dosing regimens.

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Pharmacokinetics in stable heart transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations

Cited by 25 publications

References 17 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

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

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