Conversion from twice daily tacrolimus capsules to once daily extended‐release tacrolimus (LCP‐Tacro): Phase 2 trial of stable liver transplant recipients

Alloway, Rita R.; Eckhoff, Devin E.; Washburn, W. Kenneth; Teperman, Lewis

doi:10.1002/lt.23844

Cited by 51 publications

(73 citation statements)

References 35 publications

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“…LCP-Tacro showed a numerically higher correlation between C min and area under the curve versus twice-daily tacrolimus capsules [35,43,44]. The PK profile of LCP-Tacro is characterized by flatter kinetics (i.e., less fluctuation and swing) compared to twice-daily tacrolimus (TABLE 1), resulting in a steadier concentration-time profile that is more consistently within the therapeutic range/window over 24 h. Reduced fluctuations in drug plasma concentrations may result in a more continuous effect and the avoidance of high peak concentrations may reduce the incidence and/or intensity of drug toxicity-related adverse events.…”

Section: Pks and Metabolismmentioning

confidence: 99%

“…In addition to the increased tacrolimus bioavailability associated with LCP-Tacro, the reduced peak-to-trough found for LCP-Tacro compared to twice-daily tacrolimus capsules and the inter-day reproducibility in PK suggest a tighter and more consistent relationship between the dose given and the tacrolimus exposure level for LCP-Tacro compared to twice-daily tacrolimus capsules [35]. 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].…”

Section: Pks and Metabolismmentioning

confidence: 99%

“…Following study enrollment, each patient was monitored for 7 days on a fixed dose of tacrolimus capsules twice-daily to ensure stable tacrolimus trough concentrations between 5 and 12 ng/ml [43]. On Day 8, each patient was converted to once-daily LCPTacro tablets using a dose conversion ratio targeting of 0.70, and ranging from 0.66 to 0.80; patients continued on a fixed dose of once-daily LCP-Tacro for days 8-21.…”

Section: Liver Transplantationmentioning

confidence: 99%

See 2 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

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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: Pks and Metabolismmentioning

confidence: 99%

Section: Pks and Metabolismmentioning

confidence: 99%

Section: Liver Transplantationmentioning

confidence: 99%

See 1 more Smart Citation

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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“…The C max , C max /C min ratio, percent fluctuation and swing were significantly (P < .001) lower and T max significantly lower (P < .001) for LCP-TAC versus TAC-IR [13].…”

Section: Discussionmentioning

confidence: 89%

“…Dosage details are shown in paper. Reproduced from Gaber et al [12] and Alloway et al [13], with permission.…”

Section: Discussionmentioning

confidence: 99%

Meltdose Tacrolimus Pharmacokinetics

Baraldo

2016

Transplantation Proceedings

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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

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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.

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Conversion from twice daily tacrolimus capsules to once daily extended‐release tacrolimus (LCP‐Tacro): Phase 2 trial of stable liver transplant recipients

Cited by 51 publications

References 35 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

Meltdose Tacrolimus Pharmacokinetics

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

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