Sublingual Administration of Tacrolimus: Current Trends and Available Evidence

Abstract

Widespread anecdotal use of sublingual tacrolimus administration has arisen, although little literature exists to guide practice. Given the paucity of data, we conducted a survey to evaluate the practice of sublingual tacrolimus administration at transplant centers across the United States and evaluated the literature that is currently available. A 10-question online survey assessing the current state of sublingual tacrolimus use was distributed to pharmacists at transplant centers that each performed more than 100 solid organ transplantations in 2013. In addition, a literature review was performed by searching the PubMed database to identify available evidence for the sublingual administration of tacrolimus. The online survey was completed by 59 (65.6%) of the 90 targeted transplant centers, representing 51.3% of all solid organ transplantations performed in 2013. Sublingual administration of tacrolimus was used in all solid organ transplant populations, with ~67% of lung transplant centers using this route for tacrolimus. The most common dose conversion was 2 mg oral to 1 mg sublingual, with 92% of centers opening oral capsules and administering the contents sublingually. Home use of sublingual administration and use in the pediatric population was uncommon. Seven peer-reviewed reports and one abstract were identified in the literature review. Seven of the eight publications reported favorably on sublingual administration, although no consistent dose conversion or method of administration was elucidated. The majority of the transplant centers surveyed found sublingual tacrolimus a viable alternative when oral administration is unavailable. A large robust prospective evaluation of sublingual administration of tacrolimus is imperative to provide the most effective care to solid organ transplant recipients and to ensure optimal safety for both patients and providers who administer the drug.

High Variability of Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

“…In general, tacrolimus is orally dosed after thoracic organ transplantation even when gut dysmotility ensues, because tacrolimus has known nephrotoxicity and intravenous administration may cause additional nephrotoxicity due to the use of the solvent HCO-60 [1,2]. When the oral route is not feasible, sublingual administration has been recommended over intravenous administration by some authors, though this is not sufficiently substantiated yet and is therefore not common practice [27].…”

Prior Amiodarone Exposure Reduces Tacrolimus Dosing Requirements in Heart Transplant Recipients

“…Sublingual doses were converted to oral equivalents using the ratio of 1:2, and continuous infusion doses were converted using the ratio of 1:4. 8,9 Secondary end points include the incidence of acute cellular rejection, acute kidney injury, total hospital length of stay, and mortality within 6 months following transplantation. Acute cellular rejection was defined as histopathologic evidence grade 2R or higher on endomyocardial biopsy; episodes of hemodynamic decompensation or echocardiographic evidence of graft dysfunction in the setting of a negative biopsy were counted if the patient received treatment (eg, pulse steroids).…”

Determining the conversion ratios for oral versus sublingual administration of tacrolimus in solid organ transplant recipients

“…It is well established that tacrolimus requires frequent therapeutic drug monitoring, and the conversion between SL and oral administration requires dosage adjustment . Based on the median values in our study population, approximately 120%‐130% of the SL dose achieves blood concentrations that are equivalent in heart, kidney, and lung transplant recipients, while oral administration of tacrolimus given at approximately 160% of the SL dose achieves blood concentrations that are equivalent in liver transplant recipients.…”

“…Tacrolimus is a calcineurin inhibitor that is a core component of the immunosuppression regimen following solid organ transplantation . Tacrolimus exerts its effects by blocking the transcription of cytokines essential for T‐cell activation, including interleukin‐2 . Tacrolimus undergoes extensive hepatic and intestinal metabolism via cytochrome P‐450 (CYP) 3A4 and 3A5 isoenzymes as well as the P glycoprotein (PGP) efflux pump.…”

“…Previous studies have established the safety and efficacy of tacrolimus SL route of administration . Other studies have assessed the conversion from oral to SL or vice versa but have shown inconsistent results .…”