Elsevier

Transplantation Proceedings

Volume 42, Issue 10, December 2010, Pages 4331-4337
Transplantation Proceedings

Thoracic transplantation
Sublingual Tacrolimus as an Alternative to Intravenous Route in Patients With Thoracic Transplant: A Retrospective Study

https://doi.org/10.1016/j.transproceed.2010.09.126Get rights and content

Abstract

Tacrolimus (TRL) is an immunosuppressive drug characterized by a narrow therapeutic index, low bioavailability, and pharmacokinetic variability. Intravenous (IV) TRL may be needed whenever the oral route is unavailable. The small amount of infusion formulation (5 mg/mL) results in a large dilution and need for careful technical management of the infusion. This study addressed the feasibility to provide sublingual (SL) as an alternative to IV. TRL for transplanted patients.

In a substudy, we performed a retrospective analysis of 17 lung and heart transplant patients using SL TRL. It included therapeutic drug monitoring and 4 area under curve (AUC) measurements. Patients received SL TRL on a dose-to-dose basis from the oral formulation. The mean age of the subjects (14 male, 3 female) was 35.3 ± 15.6 years; 146 trough (C0) samples were collected during the SL period (15.8 ± 20.6 days) showing a conformity level of 90.4%. Mean dose, C0, and AUC of SL tacrolimus were 0.116 ± 0.096 mg/kg, 12.9 ± 5 ng/mL, and 230 ± 74 ng · h/mL, respectively, with an average 1 hour time to peak concentration. Acute rejection episodes, renal toxicity, and drug interactions were not observed. This study supported the convenience of short-term SL TRL administration, even in unconscious patients. Further investigations are needed to validate the dose range of the SL route.

Section snippets

Patients

This retrospective longitudinal study was performed from 2005 to 2008 in eligible patients who received SL TRL administration during their hospitalization because the oral route was unavailable. Patients were followed with therapeutic drug monitoring to adjust dosing to blood concentrations of TRL. The feasibility of the SL route of TRL administration was documented in a few patients undergoing rich pharmacokinetic sampling.27

Modality of Sublingual Tacrolimus Administration

Sublingual TRL administration was performed using Prograf oral

Blood Concentration Assessments

Blood levels were analyzed using the tacrolimus II assay (IMx, Abbott, Chicago, Illinois, USA) based on microparticle enzyme immunoassay technology. The test quantitatively estimates TRL concentration of 3–30 ng/mL. The analytic limit of detection of the test amounts to 1.2 ng/mL, whereas its functional limit of quantification at 20% coefficient of variation amounts to 1.4 ng/mL. Whole blood samples were collected with EDTA venous blood collection. Those samples which were an integral part of

Patients

In our cohort, 16 patients received SL tacrolimus, representing 17 clinical TDMs. Table 1 summarizes their major demographic data and the clinical rationale for use of the SL as an alternative to the IV route. The mean age of the patients was 35 ± 17 years, with predominantly a male distribution (n = 13). The main recipients were lung transplant patients (n = 13), with 10 (71.4%) bilateral lung transplants because of end-stage cystic fibrosis. Gastrointestinal disorders represented the most

Discussion

This study showed the potential benefit and safety of the TRL SL route as an alternative to the IV route for short-term therapy. TRL is a strong immunosuppressant with narrow therapeutic range. Monitored therapy plays an important role to control for efficacy versus adverse effects, such as nephrotoxicity and neurotoxicity. TRL overexposure is also accompanied by increased immunosuppressive effects, which can lead to an increased risk of opportunistic infections and malignancies.28, 29, 31, 33,

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