Tacrolimus Once Daily (ADVAGRAF) Versus Twice Daily (PROGRAF) in De Novo Renal Transplantation: A Randomized Phase III Study

Krämer, Bernhard K.; Charpentier, B; Bäckman, Lars; Silva, H. Tedesco; Mondragón-Ramírez, Guillermo; Cassuto‐Viguier, E.; Mourad, Georges; Solá, Ricard; Rigotti, Paolo; Mirete, J. Ortuño

doi:10.1111/j.1600-6143.2010.03256.x

Cited by 162 publications

(157 citation statements)

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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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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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“…More recently, Krämer and associates published another phase 3 double-blind randomized study in which 667 new kidney recipients received either OD or twice-daily tacrolimus combined with steroids and low-dose mycophenolate. 8 In the per-protocol analysis, the incidence of biopsy-proven acute rejection was slightly higher with tacrolimus OD over 24 weeks (20.4% vs 15.8%; not significant). Graft function, graft loss, patient survival, and adverse reaction profiles were similar among the 2 groups.…”

Section: Discussionmentioning

confidence: 99%

“…These observations are similar to previous published studies. [4][5][6][7][8][9][10][11] We usually do not use ER tacrolimus as induction in de novo kidney transplants as the dosage of tacrolimus is easier to adjust with the twice-daily formulation. However, OD tacrolimus can be useful in patients in whom we want to decrease the initial exposure to calcineurin inhibitors (eg, severe acute tubular necrosis).…”

Section: Discussionmentioning

confidence: 99%

“…9 Trials are summarized in Table 4. [4][5][6][7][8][9][10][11] We were one of the first transplant centers in Canada to switch twice-daily to OD ER tacrolimus in stable kidney transplants who had been followed-up for 2 years. Despite the observational nature of our study and the absence of a control group, we demonstrated that conversion to ER tacrolimus was safe and convenient in one-third of kidney transplant recipients.…”

Section: Discussionmentioning

confidence: 99%

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Tran

Vallée²,

Collette³

et al. 2014

Exp Clin Transplant

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Objectives: Tacrolimus extended-release formulation has been approved for use in Canada since October 2008. In initial studies, efficacy and safety profile were demonstrated as similar for both formulations (twice-daily tacrolimus and extended-release formula tacrolimus). To validate the safety and efficacy of extended-release formula tacrolimus, we conducted a prospective observational study. Materials and Methods: At our institution, between January 2009 and January 2010, the switch from tacrolimus to extended-release formula tacrolimus was done in 130 stable kidney recipients. Clinical data were accessed at baseline (data before conversion), 1 to 2 weeks, 1 month, 3 months, 6 months, 12 months, and 24 months after conversion. Results: One hundred thirty renal transplant recipients were included in the current study. During the observation period, we saw no acute rejection and no change in graft function (mean serum creatinine levels remained stable). However, compared with baseline, mean tacrolimus trough levels were significantly reduced at 1 to 2 weeks, at 1 month, 6 months, 12 months, and at 24 months after conversion. Regarding the safety profile, no significant changes were noted in blood glucose, potassium, and magnesium. Approximately 35% of recipients preferred the extended-release formula tacrolimus to twice-daily tacrolimus. Conclusions: Conversion from twice-daily tacrolimus to extended-release once-daily tacrolimus appears to be safe and convenient up to 2 years after conversion in some recipients.

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“…Most previous pharmacokinetics studies comparing twice-daily and once-daily tacrolimus in de novo transplant recipients have reported that, after once-daily tacrolimus administration, C min values are reduced in the immediate posttransplant period and higher doses of the drug are required to maintain target concentrations. 9,24,25 A previous multicenter comparison of the safety and efficacy of tacrolimus administered once-versus twice-daily to de novo LDLT recipients also demonstrated lower C min values and a higher dose requirement for once daily tacrolimus than for twice-daily tacrolimus when normalized to mr doses of tacrolimus (unpublished data). Here, a higher dose of once-daily tacrolimus was required to maintain target concentrations during the posttransplant period, especially immediately after the conversion from intravenous to oral administration of the drug.…”

Section: Figure 1 Liver Transplantation At Başkent Universitymentioning

confidence: 99%

Untitled

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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Tacrolimus Once Daily (ADVAGRAF) Versus Twice Daily (PROGRAF) in De Novo Renal Transplantation: A Randomized Phase III Study

Cited by 162 publications

References 26 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

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