Novel Once-Daily Extended-Release Tacrolimus (LCPT) Versus Twice-Daily Tacrolimus in De Novo Kidney Transplants: One-Year Results of Phase III, Double-Blind, Randomized Trial

Budde, Klemens; Bunnapradist, Suphamai; Grinyó, Josep M.; Ciechanowski, Kazimierz; Denny, Jason E; Silva, H. T.; Rostaing, Lionel

doi:10.1111/ajt.12955

Cited by 104 publications

(161 citation statements)

References 20 publications

Supporting

Mentioning

141

Contrasting

Unclassified

Order By: Relevance

“…In Phase II studies in which stable kidney or liver transplant recipients were converted from twice-daily tacrolimus capsules to once-daily LCP-Tacro tablets, an approximate 20% [45] to 30% [35,43] lower dose of LCP-Tacro resulted in similar AUC 24 as twice-daily tacrolimus capsules. This was further confirmed by post-hoc analysis in a Phase III de novo clinical trial [46]. A prolonged time to peak was also consistently demonstrated during Phase II trials, potentially decreasing the risk of overlapping of peak toxicities with other co-medications (e.g., mycophenolate mofetil [47]/ mycophenolic acid [48]) In addition, LCP-Tacro showed similar PK regardless if administered in the morning or evening [49].…”

Section: Pks and Metabolismmentioning

confidence: 71%

“…Tacrolimus trough levels were notably higher in the LCP-Tacro group compared with the tacrolimus twice-daily group in the first 2 weeks after dosing; thereafter, trough levels in the two groups were similar through month 12 [46].…”

Section: Drug Profilementioning

confidence: 84%

“…As stated in the Kidney Disease: Improving Global Outcomes clinical practice guideline for the care of kidney transplant recipients, the earlier that therapeutic blood levels of a CNI can be attained, the more effective the CNI will be in preventing acute rejection [12]. Clinical data show that LCP-Tacro is associated with rapid and consistent exposure (AUC), with lower total daily tacrolimus dose in both kidney and liver transplant recipients who were converted from twice-daily tacrolimus capsules to once-daily prolonged release MeltDose tacrolimus tablets [35,45], and in de novo kidney transplant recipients [46]. As a result of the increased bioavailability afforded by LCP-Tacro, therapeutic tacrolimus levels are more rapidly achieved with LCP-Tacro compared to twice-daily tacrolimus capsules.…”

Section: Pks and Metabolismmentioning

confidence: 99%

“…Two randomized Phase III trials and one Phase IIIb trial have been completed to date (TABLE 3) [46,56]. Study 3001 (MELT trial) was an open-label, multicenter, prospective, randomized, two-arm parallel group study in stable kidney transplant patients.…”

Section: Phase III Studiesmentioning

confidence: 99%

“…Study 3002 was a double-blind, double-dummy, multicenter, prospective, randomized, two-arm parallel group study in which adult de novo kidney transplant patients were randomized to receive either once-daily LCP-Tacro at a starting dose of 0.17 mg/kg/day or twice-daily tacrolimus capsules at a starting dose of 0.1 mg/kg/day for 24 months [46]. After receiving the initial starting dose, the dose could then be adjusted to maintain tacrolimus whole blood trough levels within the predefined therapeutic range of 6-11 ng/ml for the first 30 days of the study, and 4-11 ng/ml for the remainder of the study [46].…”

Section: Phase III Studiesmentioning

confidence: 99%

See 4 more Smart Citations

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

View full text Add to dashboard Cite

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 ...

show abstract

Section: Pks and Metabolismmentioning

confidence: 71%

Section: Drug Profilementioning

confidence: 84%

Section: Pks and Metabolismmentioning

confidence: 99%

Section: Phase III Studiesmentioning

confidence: 99%

Section: Phase III Studiesmentioning

confidence: 99%

See 3 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

Liver Transplantation: Prevention and Treatment of Rejection

Durand

Francoz

2019

Evidence‐based Gastroenterology and Hepatology 4e

View full text Add to dashboard Cite

Pharmacokinetics of Once‐Daily Extended‐Release Tacrolimus Tablets Versus Twice‐Daily Capsules in De Novo Liver Transplant

DuBay

Teperman

Ueda

et al. 2019

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

The pharmacokinetics of once‐daily extended‐release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open‐label study, de novo liver transplant recipients were randomized to LCPT 0.07–0.13 mg/kg/day (taken once daily; n = 29) or twice‐daily immediate‐release tacrolimus capsules (IR‐Tac) at 0.10–0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentrations of 5 to 20 ng/mL through day 90, and 5–15 ng/mL thereafter. Twenty‐four‐hour pharmacokinetic profiles were obtained on days 1, 7, and 14, with trough concentration and efficacy/safety monitoring through year 1. Similar proportions of patients in both groups achieved therapeutic trough concentrations on days 7 and 14 (day 7: LCPT = 78%, IR‐Tac = 75%; day 14: LCPT = 86%, IR‐Tac = 91%) as well as similar systemic and peak exposure. There was a robust correlation between drug concentration at time 0 and area under the concentration‐time curve for both LCPT and IR‐Tac (respectively, day 7: r = 0.86 and 0.79; day 14: r = 0.93 and 0.86; P < .0001 for all). Dose adjustments during days 1 to 14 were frequent. Thirty‐five patients completed the extended‐use period. No significant differences in adverse events were seen between groups. Incidence of biopsy‐proven acute rejection (LCPT = 6 and IR‐Tac = 4) was similar on day 360. Between formulations, overall exposure was similar at 1 week after transplant with the characteristic delayed‐release pharmacokinetic profile of LCPT demonstrated in this novel population. These data support further investigation of the safety and efficacy of LCPT in de novo liver transplantation.

show abstract

Novel Once-Daily Extended-Release Tacrolimus (LCPT) Versus Twice-Daily Tacrolimus in De Novo Kidney Transplants: One-Year Results of Phase III, Double-Blind, Randomized Trial

Cited by 104 publications

References 20 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

Liver Transplantation: Prevention and Treatment of Rejection

Pharmacokinetics of Once‐Daily Extended‐Release Tacrolimus Tablets Versus Twice‐Daily Capsules in De Novo Liver Transplant

Contact Info

Product

Resources

About