MeltDose Technology vs Once-Daily Prolonged Release Tacrolimus in De Novo Liver Transplant Recipients

Baccarani, Umberto; Velkoski, Jaqueline; Pravisani, Riccardo; Adani, Gian Luigi; Lorenzin, Dario; Cherchi, Vittorio; Falzone, Bruno; Baraldo, Massimo; Risaliti, Andrea

doi:10.1016/j.transproceed.2019.03.084

Cited by 8 publications

(14 citation statements)

References 7 publications

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“…There are very few studies in the literature investigating liver transplant recipients newly initiated on LCPT [ 15 , 16 ], and our findings are in line with previous reports. The pharmacokinetics, safety, and efficacy of LCPT in de novo LCPT users with liver transplants were investigated in a phase 2 randomized study.…”

Section: Discussionsupporting

confidence: 93%

“…Approximately two-thirds of the patients in each group had therapeutic trough levels after 14 days, albeit with fewer dose adjustments in the LCPT group (3.9/patient versus 4.8/patient). A single-center, retrospective study compared LCPT with the once-daily prolonged-release tacrolimus (PR-tac) formulation Advagraf ® during the first 30 days after transplant [ 16 ]. LCPT resulted in faster attainment of therapeutic trough levels than comparable doses of the PR-tac formulation; after stabilization, the maintenance LCPT dose was 25% than the PR-tac formulation [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

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A Multi-Centre Non-Interventional Study to Assess the Tolerability and Effectiveness of Extended-Release Tacrolimus (LCPT) in De Novo Liver Transplant Patients

Soliman

Gyoeri

Salat

et al. 2023

JCM

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Background: Available tacrolimus formulations exhibit substantial inter- and intra-individual variability in absorption and metabolism. The present non-interventional cohort study aimed to assess the tolerability and effectiveness of the once-daily tacrolimus formulation, LCPT, in hepatic allograft recipients in real life. Materials and methods: This study was conducted in Austria and the Czech Republic between July 2016 and August 2019. Patients aged ≥ 18 years old received LCPT per the approved label and local clinical routine. All the participants provided informed consent. Patients newly treated with tacrolimus (de novo) directly after transplantation were observed for six months. The relevant clinical variables were tacrolimus trough level (TL), total daily dose (TDD), number of dose adjustments, kidney and liver function, and tolerability. Results: Of the 70 analyzed patients, 72.9% were male and 85.7% were aged < 65 years old. The mean (SD) time to achieve tacrolimus target TL was 6.4 (4.6) days after 4.4 (4.0) dose adjustments; thereafter, TL remained stable throughout observation at approximately 8 ng/mL. The LCPT TDD at initiation was 8 mg and decreased by a median of 41.4% to 5 mg at 6 months. Liver function continuously improved, and kidney function remained stable. LCPT was well tolerated with 24 adverse events in eight patients (17 related to immunosuppression, mostly mild renal insufficiency, and hematological adverse events); two serious unrelated adverse events were reported (atrial flutter and liver dysfunction). Conclusions: TL was rapidly attained with few dose adaptations after LCPT initiation in de novo liver transplant patients. Liver function rapidly improved, whereas kidney function remained normal. LCPT was well-tolerated in this population.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

A Multi-Centre Non-Interventional Study to Assess the Tolerability and Effectiveness of Extended-Release Tacrolimus (LCPT) in De Novo Liver Transplant Patients

Soliman

Gyoeri

Salat

et al. 2023

JCM

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“…Therapeutic trough levels were obtained faster under treatment with LCP-Tac and, additionally, patients given LCP-Tac required a 25% lower median dose to maintain the same therapeutic trough levels as patients treated with PR-Tac. 18 With a significantly higher ratio C 0 /dose ss for LCP-Tac compared to PR-Tac in our work presented here, we confirm that less dose of LCP-Tac is required to achieve a comparable trough level. Furthermore, a lower cumulative Tac dose per day was observed in our de novo liver transplant recipients receiving LCP-Tac than in patients administered PR-Tac.…”

Section: Discussionsupporting

confidence: 81%

A single‐center, open‐label, randomized cross‐over study to evaluate the pharmacokinetics and bioavailability of once‐daily prolonged‐release formulations of tacrolimus in de novo liver transplant recipients

Herden

Sterneck

Buchholz

et al. 2021

Immunity Inflam & Disease

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Background: The narrow therapeutic window of tacrolimus (Tac) requires intense drug monitoring to achieve adequate efficacy while minimizing dose-related toxicities. Once-daily formulations of Tac (LCP-Tac and PR-Tac) have been recently designed for higher bioavailability and a more consistent exposure over time, as opposed to the twice-daily, administered immediate-release formulation of Tac (IR-Tac). Methods: This single-center, open-label, randomized cross-over pharmacokinetic (PK) study compares extended-release LCP-Tac with the prolonged-release formulation of tacrolimus (PR-Tac) in adult de novo liver transplant recipients.Eligible patients were screened and randomized 1:1 to the two treatment arms up to 30 days after liver transplantation. Patients were administered either LCP-Tac or PR-Tac for 14 days followed by another 14-day time interval of the other once-daily Tac medication. A 24hr-PK profile was obtained at the end of each time interval.Results: Nine patients (45%) completed the study resulting in a total of 18 Tac PK profiles. Overall, the profile of the mean concentrations indicated a flattened kinetic of LCP-Tac compared to PR-Tac, especially in the first 3 h after drug intake. The average cumulative dose per day to achieve equivalent trough levels was approximately 25% lower for LCP-Tac (8.7 mg) than for PR-Tac (11.7 mg). LCP-Tac resulted in a longer t max and fewer peak-to-trough fluctuations compared to PR-Tac. Conclusion: Despite methodological weaknesses that limit the conclusions, we have found a more consistent drug exposure for LCP-Tac in de novo LT recipients. LCP-Tac demonstrated a greater bioavailability compared to PR-Tac.

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“…In a phase 2 study conducted on stable LTx patients (28), pharmacokinetic data demonstrated consistent exposure at a lower conversion dose. In 2019, Baccarani et al (22) retrospectively compared Envarsus® versus Advagraf™ in de novo LTx recipients, focusing on administered daily dose and therapeutic trough levels during the rst 30 days after transplant. Using Envarsus® resulted in faster achievement of therapeutic trough levels.…”

Section: Discussionmentioning

confidence: 99%

“…It is widely reported that switching kidney transplant recipients to Envarsus ® elevates the C/D ratio (20), since lower drug doses are su cient to maintain therapeutic trough levels with this galenic drug formulation. Data from observational studies show that a higher C/D ratio can also be achieved when using this drug in LTx recipients (21,22). Since bioavailability studies on Envarsus ® in the context of LTx are less prevalent in the scienti c literature compared to kidney transplantation, and no phase III or IV studies with Envarsus ® have been conducted in de novo LTx recipients, the EnGraft Study is designed to compare the bioavailability and practicability (handling) of two once-daily tacrolimus formulations Envarsus ® versus Advagraf ™ in de novo LTx recipients over 12 weeks.…”

Section: Rationalementioning

confidence: 99%

EnGraft: a multicentre, open-label, randomised, two-arm, superiority study protocol to assess bioavailability and practicability of Envarsus® versus AdvagrafTM in liver transplant recipients

Wöhl,

James,

Götz

et al. 2022

Preprint

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Background: Graft rejection and chronic CNI toxicity remain obstacles to organ transplant success. Current formulations of tacrolimus, such as Prograf® and AdvagrafTM, exhibit limitations in terms of pharmacokinetics and tolerability, related in part to suboptimal bioavailability. As dosing non-compliance can result in graft rejection, the once daily formulation of tacrolimus, AdvagrafTM, was developed (vs 2x/day Prograf®). Benefits of AdvagrafTM are counterbalanced by delayed achievement of therapeutic trough levels and need for up to 50% higher doses to maintain Prograf®-equivalent troughs. Envarsus® is also a prolonged-release once-daily tacrolimus formulation, developed using MeltDose™ drug-delivery technology to increase drug bioavailability; improved bioavailability results in low patient drug absorption variability and less pronounced peak-to-trough fluctuations. In phase III de novo kidney transplant studies, Envarsus® proved non-inferior to twice-daily tacrolimus; however, no phase IV studies show superiority of Envarsus® vs AdvagrafTM in de novo liver transplant (LTx) recipients.Methods: The EnGraft compares bioavailability and tests superiority of Envarsus® (test arm) versus AdvagrafTM (comparator arm) in de novo LTx recipients. A total of 268 patients from 15 German transplant centres will be randomised 1:1 within 14 days post-LTx. The primary endpoint is dose-normalised trough level (C/D ratio) measured 12 weeks after randomisation. Secondary endpoints include the number of dose adjustments, time to reach first defined trough level and incidence of graft rejections. Additionally, clinical and laboratory parameters will be assessed over a 3-year period.Discussion: C/D ratio is an estimate for tacrolimus bioavailability. Improving bioavailability and increasing C/D ratio using Envarsus could reduce renal dysfunction and other tacrolimus-related toxicities; previous trials have shown that a higher C/D ratio (i.e. slower tacrolimus metabolism) is not only associated with improved renal function, but also linked to reduced neurotoxic side-effects. A higher C/D ratio could improve clinical outcomes for LTx recipients; EnGraft has begun, with one third of patients recruited by January 2022.Trial registration: This trial has been registered (4th May 2020) in the EU Clinical Trials Register, EudraCT-Nummer: 2020-000796-20. Additionally, this trial has been registered (22nd January 2021) at ClinicalTrials.gov: NCT04720326. The trial received a favourable opinion from the concerned lead ethics committee at the University of Regensburg, under the reference 20-1842-112.

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MeltDose Technology vs Once-Daily Prolonged Release Tacrolimus in De Novo Liver Transplant Recipients

Cited by 8 publications

References 7 publications

A Multi-Centre Non-Interventional Study to Assess the Tolerability and Effectiveness of Extended-Release Tacrolimus (LCPT) in De Novo Liver Transplant Patients

A Multi-Centre Non-Interventional Study to Assess the Tolerability and Effectiveness of Extended-Release Tacrolimus (LCPT) in De Novo Liver Transplant Patients

A single‐center, open‐label, randomized cross‐over study to evaluate the pharmacokinetics and bioavailability of once‐daily prolonged‐release formulations of tacrolimus in de novo liver transplant recipients

EnGraft: a multicentre, open-label, randomised, two-arm, superiority study protocol to assess bioavailability and practicability of Envarsus® versus AdvagrafTM in liver transplant recipients

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