Sublingual tacrolimus administration provides similar drug exposure to per‐oral route employing lower doses in liver transplantation: a pilot study

Solari, Sandra; Cancino, Alejandra; Wolff, Rodrigo; Norero, Blanca; Vargas, José Ignacio; Barrera, Francisco; Guerra, Juan Francisco; Martínez, Jorge; Jarufe, Nicolás; Soza, Alejandro; Arrese, Marco; Benítez, Carlos

doi:10.1111/apt.14022

Cited by 12 publications

(7 citation statements)

References 13 publications

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“…Due to its limitations, including narrow therapeutic window, poor solubility, and low bioavailability via oral administration, long-term use of FK506 needs to balance adverse effects and therapeutic efficiency in a clinical regimen. Hence, a change in the route of drug administration would be a powerful strategy to overcome its limitations (Solari et al, 2017 ; Gao et al, 2021 ). According to the literature, SC administration is a popular alternative delivery route as it provides the following advantages, such as (1) potential to avoid enteral metabolism and liver first-pass effect and to promote the effective delivery of drugs that have low oral bioavailability; (2) potential to achieve improved tolerability by minimizing the peak to trough ratio in the systemic circulation; (3) potential to achieve prolonged systemic exposure (Chiang et al, 2019 ; Lee et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Immunosuppressive effect of PLGA-FK506-NPs in treatment of acute cardiac rejection via topical subcutaneous injection

Deng

Jin

et al. 2021

Drug Delivery

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FK506, a first-line immunosuppressant, is routinely administered orally and intravenously to inhibit activation and proliferation of T cells after heart transplantation (HT). Current administration route is not conducive enough to exert its efficacy in lymphatic system. Herein, we proposed that subcutaneous (SC) administration of FK506-loaded nanoparticles (PLGA-FK506-NPs) would be valuable for treating acute rejection after HT. The biodistribution and pharmacokinetic study revealed that it could effectively deliver FK506 to the lymph nodes (LNs) due to their suitable particle size, especially in inguinal LNs. Subsequently, the therapeutic efficacy of PLGA-FK506-NPs on the HT model was evaluated using intravenous (IV), intragastric (IG), or SC injection. Histopathological analysis revealed that 80% of allografts exhibited only grade 1R rejection with negligible lymphocyte infiltration in the SC group. The IV group exhibited 40% 1R rejection with mild lymphocyte infiltration and 20% grade 3R that require further intervention, and the IG group exhibited grades 40% 3R rejection with more lymphocyte infiltration. Moreover, the infiltration of T cells and the secretion of IL-2 and IFN-γ were significantly reduced in the SC group compared with the IG or IV group. The mean survival time (MST) further revealed that 50% of grafts treated with PLGA-FK506-NPs via SC injection survived longer than IG and IV groups. Moreover, the MST of single-dose SC injection of PLGA-FK506-NPs demonstrated that it would effectively reduce the required dose for a similar therapeutic effect. Overall, these results indicate that SC administration of PLGA-FK506-NPs is a more effective route for chronic FK506 treatment.

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Section: Discussionmentioning

confidence: 99%

Immunosuppressive effect of PLGA-FK506-NPs in treatment of acute cardiac rejection via topical subcutaneous injection

Deng

Jin

et al. 2021

Drug Delivery

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“…2 They convert 32 stable liver transplant recipients >1 year after transplant from twice daily oral to sublingual tacrolimus. Despite its small sample size, the crossover nature, varied indication for transplant and pharmacokinetic sampling make this a well-done study.…”

Section: In a Recent Issue Of Alimentary Pharmacology And Therapeuticsmentioning

confidence: 99%

Editorial: tacrolimus―how low can you go?

O’Leary¹

2017

Aliment Pharmacol Ther

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content using MRS, the primary outcome, in intention-to-treat analysis. There was also a modest but statistically significant improvement in body mass index in the high-dose group compared to placebo. Patients included in the trial were primarily middle-aged, nondiabetic, men of South Korean descent limiting its generalisability to other populations. In addition, despite block randomisation the high-dose oltipraz group had the most liver fat content at baseline 38.8% vs 29.9% in the placebo group and this difference across groups was statistically significant, P=.02. In small clinical trials, stratified block randomisation or adaptive randomisation may help to avoid asymmetry in critical variables. To mitigate concern that the benefit in the oltipraz group may have been impacted by the degree of steatosis at baseline, the authors presented per cent change from baseline in liver fat and showed a trend towards improvement in the low-dose oltipraz group, which supports the compound's efficacy.The authors' chose to utilise MRS as the primary endpoint adding to a growing number of trials. transplant recipients >1 year after transplant from twice daily oral to sublingual tacrolimus. Despite its small sample size, the crossover nature, varied indication for transplant and pharmacokinetic sampling make this a well-done study. They convincingly show that sublingual administration results in a 37% lower dose of tacrolimus to achieve a similar trough concentration and AUC while the 2 hour peak concentration was significantly lower. Although not shown in this study,we would hope that a lower C MAX may lead to fewer side effects, while the maintenance of AUC and trough were shown to achieve similar efficacy.Fortunately, no patient experienced rejection or graft loss during the study, and the ability to cut the dose by one-third through sublingual administration and yet maintain the AUC and trough concentration is an attractive cost saving approach. Of note, standard twice-daily orally administered tacrolimus has been used once-daily. 3This cut the amount of medication needed to 85% of the total daily dose and achieved the same AUC and trough concentration but is not FDA approved. It is unknown if the dose of sublingual tacrolimus might further be lowered if it were administered once-daily.Although well done, the study's small sample size, absence of side effect assessment, maintenance of twice daily dosing and lack of truly long-term follow-up only allow us to conclude that once daily administration should next be evaluated. You ask: How low can you go? We unfortunately maintain a one-size fits all immunosuppression strategy for transplant patients.However, as we transplant older, sicker patients with more comorbid conditions we must strive to utilize drugs with better bioavailability to improve dosing schedules, reliability of levels, minimize side effects and optimize cost. Achieving a high level of compliance with any tacrolimus regimen will always be the most important factor in long-term rejection-free graft survival. M...

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“…the highly vascularised sublingual route of administration, may further improve the bioavailability of tacrolimus by circumventing the first-pass metabolism in the gut and liver. There are clinical studies to prove that sublingual tacrolimus is comparable to or more effective than oral administration, concerning bioavailability, in solid organ transplant patients [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Development and Characterization of Tacrolimus Tablet Formulations for Sublingual Administration

et al. 2021

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Objective: The study aimed to prepare and characterize inclusion complexes of tacrolimus with β-cyclodextrin to improve its solubility and to formulate them into sublingual fast disintegrating tablets with a view to bypass the first-pass metabolism. Methods: Tacrolimus: β-cyclodextrin inclusion complexes (1:1 and 1:2 molar proportions) were prepared using the kneading method. Their characterization was accomplished by determining the drug content, solubility, Attenuated Total Reflection-Infrared Spectroscopy (ATR-IR), Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), and powder X-Ray Diffraction analysis (pXRD). These were then formulated to fast disintegrating tablets and evaluated for precompression as well as post compressional characteristics. Results: SEM analysis showed the inclusion complexes as rough, non-porous, irregular surfaced aggregate particles. DSC and pXRD analyses confirm the crystallinity change and partial conversion to the amorphous form of the drug in the inclusion complexes. From the solubility studies, it was observed that both the inclusion complexes of 1:2 molar ratio (14.82±0.889 µg/ml) and 1:1 molar ratio (12.72±0.1004 µg/ml) improved the aqueous solubility to greater extents in comparison to that of the pure drug (3.05±0.121 µg/ml). All the tablet formulations showed good precompression and mechanical properties. The inclusion complex loaded tablets exhibited a superior drug release pattern when compared to tablets prepared with tacrolimus alone. The optimized formulation (TT3) showed an in vitro disintegration time of 34.33 s and a percent drug release of 97.87. Conclusion: The inclusion complex formulation combined with the sublingual route of administration can be expected to result in an improved bioavailability of tacrolimus by increasing its solubility and bypassing first-pass metabolism.

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Sublingual tacrolimus administration provides similar drug exposure to per‐oral route employing lower doses in liver transplantation: a pilot study

Abstract: Sublingual administration of tacrolimus is feasible and provides similar drug exposure compared with oral administration. In our study, at long-term follow-up, sublingual administration was not associated with liver transplant rejection.

Cited by 12 publications

References 13 publications

Immunosuppressive effect of PLGA-FK506-NPs in treatment of acute cardiac rejection via topical subcutaneous injection

Immunosuppressive effect of PLGA-FK506-NPs in treatment of acute cardiac rejection via topical subcutaneous injection

Editorial: tacrolimus―how low can you go?

Development and Characterization of Tacrolimus Tablet Formulations for Sublingual Administration

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