39th National Congress of the Italian Society of Organ Transplantation
General observation
Meltdose Tacrolimus Pharmacokinetics

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Abstract

Background

Nonadherence to immunosuppressive therapy contributes to the loss of grafts. One of the problem is the fractioning of immunosuppressive dose. In fact, it was demonstrated that a single daily dose (QD) is associated with an increased adherence to therapy compared with twice daily dosing (BID). Tacrolimus (TAC), calcineurin inhibitor, is one of immunosuppression pillar in organ transplantation and its action is strongly correlated with blood concentration and therefore the therapeutic drug monitoring is recommended in the guidelines. However, one of the critical points of TAC is the poor and variable bioavailability that influences immunosuppression, and is also responsible for adverse effects.

Methods

MeltDose® Technology is a new technology to improve efficacy and/or reduce side effects. This new technology applied to TAC (Envarsus® or LCP-TAC) has achieved 4 main objectives: (1) improved bioavailability, (2) reduced dose fractioning to one tablet per day, (3) limited variability concentrations of TAC, and (4) lower doses of TAC will be administered.

Results

We analyzed the pharmacokinetic profile, efficacy, and security of Envarsus®.

Section snippets

Methods

MeltDose® technology, a platform developed by Veloxis Pharmaceuticals A/S (Hørsholm, Denmark), a company founded in 2002, is a drug delivery technology used to enhance the oral bioavailability and control the release of a drug, especially low water-soluble or -insoluble drugs. The goal of this technology is to improve efficacy and/or reduce side effects. Particle size plays a vital role in bioavailability. Unlike conventional and nanocrystal drug delivery formulations, which use larger

Results

The pharmacokinetic profiles of TAC have been recently studied by Garnok-Jones [10], who compared kidney transplant recipients (KTRs) and liver transplant recipients who were stable, treated TAC-IR and converted to LCP-TAC. The total daily dosage was 5.26 versus 7.39 mg comparing the LCP-TAC versus TAC-IR with a statistically significant difference in KTRs (P < .05) but not in LTRs (4.4 vs 6.1 mg). The AUC24 (ng · h/mL) was comparable in LCP-TAC and TAC-IR without significant differences (206.7

Discussion

TAC is a calcineurin inhibitor much more potent than cyclosporine, but its bioavailability is low and variable, which this has often created problems of clinical efficacy. The LCP-TAC uses a MeltDose® technology and represents an innovation in the field of the immunosuppressive drugs. This new technology increases the amount of active ingredient that reaches the blood, ensuring the best therapeutic efficacy. Furthermore, the controlled release ensures a continuous absorption not only in the

References (16)

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    This difference may be explained by the lower CV in the LCPT group, though this was not significant. Overall, smoother peak-trough transition with delayed time to peaks allows for longer periods of immunosuppression at lower concentrations.14 While the pharmacokinetics of IR-TAC may be the driving factor for higher rates of observed acute rejection, the once-daily dosing of LCPT may allow for more flexibility in the maintenance phase of patients’ immunosuppressive regimens.

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    In fact, MeltDose® technology invented by Veloxis Pharmaceuticals A/S (Horsholm, Denmark) has been implemented for TAC under the brand name Envarsus® which further reduced the daily dose by 30% compared to earlier formulations. This technique maximizes oral bioavailability through reduction of drug to the smallest possible particles sizes into single molecules, compared to conventional as well as nano-DDS, that uses greater particles difficult for absorption (Baraldo, 2016). Till date, 1089 clinical trials have been carried out solely on TAC out of which 538 studies have been completed successfully and 214 studies are ongoing (https://clinicaltrials.gov/search/intervention=fk+506).

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    Envarsus is a recently marketed pharmaceutical form with MeltDose technology. MeltDose, developed by Veloxis Pharmaceuticals increases the bioavailability and control the release of fat-soluble drugs in delayed-release pharmaceutical forms.13 There are therefore two pharmaceutical forms of delayed-release tacrolimus currently available, Advagraf and Envarsus, which are administered once daily.

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