TY - JOUR
AU - Park, Jeong, M.
AB - Abstract Purpose Available data regarding sublingual tacrolimus were analyzed to provide recommendations for solid organ transplant recipients. Summary Tacrolimus is an immunosuppressive agent with a narrow therapeutic range that is commonly used in solid organ transplantation. Achieving and maintaining appropriate tacrolimus exposure are critical for preventing rejection and minimizing toxicity. A variety of clinical situations requiring nonoral medication delivery arise, presenting the need for reliable alternative routes of tacrolimus administration. A review of the currently available literature revealed nine reports of sublingual tacrolimus use in human subjects. Seven reported that sublingual administration could achieve comparable tacrolimus trough concentrations to oral administration, but none investigated the correlation between tacrolimus trough concentration and exposure. One study of lung transplant recipients found that approximately 50% of the oral dose was needed to obtain therapeutic trough concentrations when converted to sublingual administration. Another study of patients with end-stage renal disease identified a similar sublingual:oral dosing ratio of 1:2. When converted from oral tacrolimus in combination with clotrimazole to sublingual administration, the sublingual:oral dosing ratio was 1:1. Conclusion In addition to enteral tube and i.v. tacrolimus dosing, sublingual administration may be considered for short-term use in patients who are unable to receive medications orally. Based on the available data, it is reasonable to initiate sublingual tacrolimus at 50% of the current or anticipated oral dose in the absence of interacting medications. Dosing must be individualized, taking into consideration concomitant interacting medications, and adjusted to target levels based on therapeutic drug monitoring. Tacrolimus is commonly used for maintenance immunosuppression after solid organ transplantation, with over 85% of new transplant recipients in the United States receiving tacrolimus in combination with other immunosuppressants in 2011.1 Tacrolimus has a narrow therapeutic range, and therapeutic drug monitoring (TDM) is necessary to reduce the risks of rejection and toxicity. A correlation between trough concentration and exposure has been established for orally administered tacrolimus, and the whole blood trough concentration before the morning dose is typically used for TDM.2 Despite the routine application of TDM, no therapeutic trough tacrolimus target concentration is universally accepted in current clinical practice.3,–5 Tacrolimus is a substrate of the cytochrome P-450 (CYP) 3A4 and 3A5 isoenzymes as well as the P-glycoprotein (PGP) efflux pump. Interindividual and intraindividual variations in expression and activity of CYP3A4, CYP3A5, and PGP in the liver and intestines contribute to the highly variable pharmacokinetic profile of tacrolimus. The reported oral bioavailability of tacrolimus ranges from 5% to 93%, with an average of about 25%.2 The oral bioavailability is more unpredictable in the immediate posttransplantation period due to nausea, vomiting, gastroparesis, and ileus. The challenge of achieving target levels in patients who are likely to experience erratic absorption and have barriers to oral administration illustrates the need for alternative routes of tacrolimus administration. One possible alternative route is sublingual administration. This review analyzes the medical literature to formulate recommendations for dosing, administration, and monitoring of sublingual tacrolimus. The buccal, enteral, i.v., and rectal routes are also discussed as alternatives to oral tacrolimus administration. Literature review PubMed queries were conducted using combinations of the following search terms: tacrolimus, sublingual, suspension, enteral tube, intravenous, rectal, and buccal. Case reports, retrospective and prospective investigations of nonoral routes of tacrolimus administration published in English from January 1990 through June 2014 were included. Additional references were identified from the reference lists of published studies. The manufacturer of tacrolimus (Prograf, Astellas Pharma US, Inc., Deerfield, IL) was contacted and confirmed that it had no internal unpublished data regarding sublingual tacrolimus. Enteral, i.v., rectal, and buccal administration of tacrolimus Enteral administration Commercially available forms of tacrolimus include immediate- and extended-release 0.5-, 1-, and 5-mg capsules and 5-mg/mL i.v. solution.6,7 A tacrolimus suspension of 0.5 or 1 mg/mL may also be compounded by combining the immediate-release capsules with suspending and sweetening agents.8,–10 The suspension may be administered orally or through nasogastric and orogastric tubes as well as postpyloric enteral access sites. Compounded extemporaneous formulations offer dosing flexibility for pediatric patients as well as a convenient way to administer medication for patients who cannot swallow solid dosage forms. Although the concentration of tacrolimus absorbed from the suspension is measurable, the exposure achieved with this formulation may not be identical to that of oral capsules. When compared with historical controls who received oral tacrolimus capsules, pediatric liver transplant recipients receiving an oral tacrolimus suspension (0.5 mg/mL) had a lower maximum concentration (Cmax) and area under the concentration–time curve (AUC). Moreover, the correlation between trough concentration and exposure was lower with the oral suspension (r = 0.78) compared with oral capsules (r = 0.9).11 Administration of tacrolimus in combination with enteral nutrition has also been evaluated. A prospective study of 10 liver or lung transplant recipients receiving the contents of tacrolimus capsules through a nasoduodenal tube found that the absorption of tacrolimus was not affected by coadministration with continuous tube feedings compared with holding enteral nutrition for one hour before and eight hours after tacrolimus administration.12 I.V. administration Clinical situations precluding any enteral administration may arise in the postoperative period. In such cases, tacrolimus can be administered intravenously, which circumvents the concerns about absorption. However, caution must be used due to the increased risk of toxicities associated with this formulation, and specific administration guidelines should be developed to minimize these risks as well as ensure proper drug delivery. The i.v. formulation contains a castor oil derivative that can cause anaphylaxis.6 Although rare, Q-T interval prolongation is a serious adverse effect of tacrolimus, and i.v. administration has been associated with life-threatening arrhythmias.13 The increased exposure achieved with i.v. tacrolimus may increase the risk of common adverse effects of tacrolimus such as nephrotoxicity and neurotoxicity. This risk is more frequently associated with bolus dose infusions and can be minimized by administering i.v. tacrolimus as a continuous infusion. An investigation of 238 liver transplant recipients found that fewer patients receiving i.v. tacrolimus as a continuous infusion experienced neurotoxicity (3.3% versus 10.3%, p = 0.04) and renal failure (13% versus 18%, p value not reported) without any difference in transplant rejection compared with patients receiving a four-hour bolus dose infusion.14 The use of i.v. tacrolimus also presents challenges for accurate and safe drug delivery. The conversion ratio for oral to i.v. tacrolimus dosing is not 1:1. Based on approximate bioavailability, the dose of i.v. tacrolimus is typically one third to one fifth that of the oral dose. Consequently, preparation of relatively small i.v. doses often requires error-prone dilution. As a lipophilic compound, tacrolimus adsorbs to certain materials, such as polyvinyl chloride (PVC).15 Extraction of toxic phthalates also occurs when tacrolimus is combined with PVC. Therefore, glass or polyethylene containers are required for i.v. dispensing of the drug. For administration of very dilute solutions, such as pediatric doses, the manufacturer labeling recommends using PVC-free tubing.6 Rectal and buccal administration Experience with rectal administration in solid organ transplant recipients is limited to a single report of three kidney transplant recipients who achieved detectable tacrolimus levels after receiving rectal tacrolimus at a dose of 0.23–0.27 mg/kg.16 More recently, a single-dose crossover study was performed in 18 healthy volunteers. When compared with oral capsules, rectal tacrolimus resulted in a longer time to achieve Cmax, lower Cmax, and decreased dose-normalized AUC0–24 hr.17 One investigation of buccal tacrolimus administration in pediatric liver transplant recipients found that a similar percentage of children achieved therapeutic tacrolimus trough concentrations in the first week after transplantation when patients who received 0.5-mg/mL suspension buccally were compared with those who received the same weight-based dose of suspension through a nasogastric tube.18 Sublingual administration of tacrolimus Due to the limitations of oral, enteral, i.v., rectal, and buccal administrations of tacrolimus, the sublingual route has emerged as an attractive alternative. Currently available literature regarding sublingual tacrolimus administration is summarized in Table 1. Table 1 Published Studies of Sublingual Tacrolimusa Ref. Design Study Population Administration Technique Findings 17 Prospective, single-dose, three-period, crossover pharmacokinetics study (n = 18) Healthy volunteers received single doses of oral, rectal, or sublingual tacrolimus in randomized sequences Contents of capsule placed under tongue; subject instructed not to swallow for 15 min and then to spit and rinse mouth with water • Tacrolimus conc. undetectable (<1 μg/L) for 11 of 18 subjects after sublingual administration • Cmax for remaining 7 subjects, 1.3–22 μg/L. • Mean Cmax after oral administration, 34.5 μg/L 19 Prospective, observational study (n = 6) Lung transplant recipients with CF receiving sublingual tacrolimus immediately after transplantation for 6 mo Contents of capsule placed under tongue and allowed to dissolve completely • 74% of trough conc. > 10 ng/mL • Six episodes of BCAR observed • No adverse events associated with sublingual administration 20 Retrospective review (n = 22) Lung transplant recipients receiving sublingual tacrolimus immediately after transplantation until oral diet initiated Contents of capsule placed under tongue and allowed to dissolve completely • 77% of troughs > 10 ng/mL • 3 of 7 pts with >6 mo follow-up experienced BCAR 21 Retrospective review, pharmacokinetics study in subgroups (n = 16) Heart or lung transplant recipients receiving sublingual tacrolimus 0.5–90 mo after transplantation Contents of capsule placed under tongue; pt instructed not to swallow for at least 15 min • Sublingual:oral dosing ratio of 1:3 resulting in similar AUC • Lower Cmax and prolonged time to Cmaxwith sublingual administration • No nephrotoxicity, neurotoxicity, or ISHLT grade 2 or greater rejection • Unpleasant taste reported with sublingual administration 23 Retrospective review (n = 34) Lung transplant recipients transitioned between sublingual and oral tacrolimus who achieved therapeutic, steady-state trough levels while receiving stable dose with both routes Contents of capsule placed under tongue; pt instructed to avoid food and beverages for 30 min • Mean ± S.D. dosing conversion ratio of 0.46 ± 0.20 • No serious adverse events with sublingual administration • 1 pt experienced mucosal irritation with sublingual administration 24 Case report (n = 1) Kidney transplant recipient receiving sublingual tacrolimus in first week after transplantation and continued for 12 mo Contents of capsule placed under tongue • Trough conc. of 17.9 ng/mL with 0.1-mg/kg daily • Trough conc. of 7–15 ng/mL after dose adjusted to 0.033 mg/kg daily • AUC0–12 hr was 170.53 and 225.53 ng · hr/mL on 2 consecutive days 25 Prospective, crossover pharmacokinetics study (n = 5) Patients with ESRD awaiting kidney transplantation receiving sublingual or oral tacrolimus for 3 days Contents of capsule placed under tongue; pt instructed not to swallow for 5 min and not to eat or drink for 15 min Sublingual:oral dosing conversion ratios of 1:2 (with nystatin) and 1:1 (with clotrimazole) 28 Prospective pharmacokinetics study (n = 5) Kidney transplantation candidates, CF pt, and healthy volunteer Contents of capsule placed under tongue; subject instructed not to swallow for 15 min and then to spit and rinse mouth with water Tacrolimus levels almost undetectable when mouth rinsed after sublingual administration 29 Prospective, crossover pharmacokinetics study (n = 6) Liver transplants within the first week after transplantation 1-mg/mL suspension administered under tongue drop by drop over 10 min; pt instructed to avoid swallowing during administration • Variable pharmacokinetic values • No differences in mean trough and AUC with sublingual vs. oral administration. Ref. Design Study Population Administration Technique Findings 17 Prospective, single-dose, three-period, crossover pharmacokinetics study (n = 18) Healthy volunteers received single doses of oral, rectal, or sublingual tacrolimus in randomized sequences Contents of capsule placed under tongue; subject instructed not to swallow for 15 min and then to spit and rinse mouth with water • Tacrolimus conc. undetectable (<1 μg/L) for 11 of 18 subjects after sublingual administration • Cmax for remaining 7 subjects, 1.3–22 μg/L. • Mean Cmax after oral administration, 34.5 μg/L 19 Prospective, observational study (n = 6) Lung transplant recipients with CF receiving sublingual tacrolimus immediately after transplantation for 6 mo Contents of capsule placed under tongue and allowed to dissolve completely • 74% of trough conc. > 10 ng/mL • Six episodes of BCAR observed • No adverse events associated with sublingual administration 20 Retrospective review (n = 22) Lung transplant recipients receiving sublingual tacrolimus immediately after transplantation until oral diet initiated Contents of capsule placed under tongue and allowed to dissolve completely • 77% of troughs > 10 ng/mL • 3 of 7 pts with >6 mo follow-up experienced BCAR 21 Retrospective review, pharmacokinetics study in subgroups (n = 16) Heart or lung transplant recipients receiving sublingual tacrolimus 0.5–90 mo after transplantation Contents of capsule placed under tongue; pt instructed not to swallow for at least 15 min • Sublingual:oral dosing ratio of 1:3 resulting in similar AUC • Lower Cmax and prolonged time to Cmaxwith sublingual administration • No nephrotoxicity, neurotoxicity, or ISHLT grade 2 or greater rejection • Unpleasant taste reported with sublingual administration 23 Retrospective review (n = 34) Lung transplant recipients transitioned between sublingual and oral tacrolimus who achieved therapeutic, steady-state trough levels while receiving stable dose with both routes Contents of capsule placed under tongue; pt instructed to avoid food and beverages for 30 min • Mean ± S.D. dosing conversion ratio of 0.46 ± 0.20 • No serious adverse events with sublingual administration • 1 pt experienced mucosal irritation with sublingual administration 24 Case report (n = 1) Kidney transplant recipient receiving sublingual tacrolimus in first week after transplantation and continued for 12 mo Contents of capsule placed under tongue • Trough conc. of 17.9 ng/mL with 0.1-mg/kg daily • Trough conc. of 7–15 ng/mL after dose adjusted to 0.033 mg/kg daily • AUC0–12 hr was 170.53 and 225.53 ng · hr/mL on 2 consecutive days 25 Prospective, crossover pharmacokinetics study (n = 5) Patients with ESRD awaiting kidney transplantation receiving sublingual or oral tacrolimus for 3 days Contents of capsule placed under tongue; pt instructed not to swallow for 5 min and not to eat or drink for 15 min Sublingual:oral dosing conversion ratios of 1:2 (with nystatin) and 1:1 (with clotrimazole) 28 Prospective pharmacokinetics study (n = 5) Kidney transplantation candidates, CF pt, and healthy volunteer Contents of capsule placed under tongue; subject instructed not to swallow for 15 min and then to spit and rinse mouth with water Tacrolimus levels almost undetectable when mouth rinsed after sublingual administration 29 Prospective, crossover pharmacokinetics study (n = 6) Liver transplants within the first week after transplantation 1-mg/mL suspension administered under tongue drop by drop over 10 min; pt instructed to avoid swallowing during administration • Variable pharmacokinetic values • No differences in mean trough and AUC with sublingual vs. oral administration. a CF = cystic fibrosis, BCAR = biopsy-confirmed acute rejection, AUC = area under the concentration–time curve, Cmax = maximum concentration, ISHLT = International Society of Heart and Lung Transplantation, ESRD = end-stage renal disease. Open in new tab Table 1 Published Studies of Sublingual Tacrolimusa Ref. Design Study Population Administration Technique Findings 17 Prospective, single-dose, three-period, crossover pharmacokinetics study (n = 18) Healthy volunteers received single doses of oral, rectal, or sublingual tacrolimus in randomized sequences Contents of capsule placed under tongue; subject instructed not to swallow for 15 min and then to spit and rinse mouth with water • Tacrolimus conc. undetectable (<1 μg/L) for 11 of 18 subjects after sublingual administration • Cmax for remaining 7 subjects, 1.3–22 μg/L. • Mean Cmax after oral administration, 34.5 μg/L 19 Prospective, observational study (n = 6) Lung transplant recipients with CF receiving sublingual tacrolimus immediately after transplantation for 6 mo Contents of capsule placed under tongue and allowed to dissolve completely • 74% of trough conc. > 10 ng/mL • Six episodes of BCAR observed • No adverse events associated with sublingual administration 20 Retrospective review (n = 22) Lung transplant recipients receiving sublingual tacrolimus immediately after transplantation until oral diet initiated Contents of capsule placed under tongue and allowed to dissolve completely • 77% of troughs > 10 ng/mL • 3 of 7 pts with >6 mo follow-up experienced BCAR 21 Retrospective review, pharmacokinetics study in subgroups (n = 16) Heart or lung transplant recipients receiving sublingual tacrolimus 0.5–90 mo after transplantation Contents of capsule placed under tongue; pt instructed not to swallow for at least 15 min • Sublingual:oral dosing ratio of 1:3 resulting in similar AUC • Lower Cmax and prolonged time to Cmaxwith sublingual administration • No nephrotoxicity, neurotoxicity, or ISHLT grade 2 or greater rejection • Unpleasant taste reported with sublingual administration 23 Retrospective review (n = 34) Lung transplant recipients transitioned between sublingual and oral tacrolimus who achieved therapeutic, steady-state trough levels while receiving stable dose with both routes Contents of capsule placed under tongue; pt instructed to avoid food and beverages for 30 min • Mean ± S.D. dosing conversion ratio of 0.46 ± 0.20 • No serious adverse events with sublingual administration • 1 pt experienced mucosal irritation with sublingual administration 24 Case report (n = 1) Kidney transplant recipient receiving sublingual tacrolimus in first week after transplantation and continued for 12 mo Contents of capsule placed under tongue • Trough conc. of 17.9 ng/mL with 0.1-mg/kg daily • Trough conc. of 7–15 ng/mL after dose adjusted to 0.033 mg/kg daily • AUC0–12 hr was 170.53 and 225.53 ng · hr/mL on 2 consecutive days 25 Prospective, crossover pharmacokinetics study (n = 5) Patients with ESRD awaiting kidney transplantation receiving sublingual or oral tacrolimus for 3 days Contents of capsule placed under tongue; pt instructed not to swallow for 5 min and not to eat or drink for 15 min Sublingual:oral dosing conversion ratios of 1:2 (with nystatin) and 1:1 (with clotrimazole) 28 Prospective pharmacokinetics study (n = 5) Kidney transplantation candidates, CF pt, and healthy volunteer Contents of capsule placed under tongue; subject instructed not to swallow for 15 min and then to spit and rinse mouth with water Tacrolimus levels almost undetectable when mouth rinsed after sublingual administration 29 Prospective, crossover pharmacokinetics study (n = 6) Liver transplants within the first week after transplantation 1-mg/mL suspension administered under tongue drop by drop over 10 min; pt instructed to avoid swallowing during administration • Variable pharmacokinetic values • No differences in mean trough and AUC with sublingual vs. oral administration. Ref. Design Study Population Administration Technique Findings 17 Prospective, single-dose, three-period, crossover pharmacokinetics study (n = 18) Healthy volunteers received single doses of oral, rectal, or sublingual tacrolimus in randomized sequences Contents of capsule placed under tongue; subject instructed not to swallow for 15 min and then to spit and rinse mouth with water • Tacrolimus conc. undetectable (<1 μg/L) for 11 of 18 subjects after sublingual administration • Cmax for remaining 7 subjects, 1.3–22 μg/L. • Mean Cmax after oral administration, 34.5 μg/L 19 Prospective, observational study (n = 6) Lung transplant recipients with CF receiving sublingual tacrolimus immediately after transplantation for 6 mo Contents of capsule placed under tongue and allowed to dissolve completely • 74% of trough conc. > 10 ng/mL • Six episodes of BCAR observed • No adverse events associated with sublingual administration 20 Retrospective review (n = 22) Lung transplant recipients receiving sublingual tacrolimus immediately after transplantation until oral diet initiated Contents of capsule placed under tongue and allowed to dissolve completely • 77% of troughs > 10 ng/mL • 3 of 7 pts with >6 mo follow-up experienced BCAR 21 Retrospective review, pharmacokinetics study in subgroups (n = 16) Heart or lung transplant recipients receiving sublingual tacrolimus 0.5–90 mo after transplantation Contents of capsule placed under tongue; pt instructed not to swallow for at least 15 min • Sublingual:oral dosing ratio of 1:3 resulting in similar AUC • Lower Cmax and prolonged time to Cmaxwith sublingual administration • No nephrotoxicity, neurotoxicity, or ISHLT grade 2 or greater rejection • Unpleasant taste reported with sublingual administration 23 Retrospective review (n = 34) Lung transplant recipients transitioned between sublingual and oral tacrolimus who achieved therapeutic, steady-state trough levels while receiving stable dose with both routes Contents of capsule placed under tongue; pt instructed to avoid food and beverages for 30 min • Mean ± S.D. dosing conversion ratio of 0.46 ± 0.20 • No serious adverse events with sublingual administration • 1 pt experienced mucosal irritation with sublingual administration 24 Case report (n = 1) Kidney transplant recipient receiving sublingual tacrolimus in first week after transplantation and continued for 12 mo Contents of capsule placed under tongue • Trough conc. of 17.9 ng/mL with 0.1-mg/kg daily • Trough conc. of 7–15 ng/mL after dose adjusted to 0.033 mg/kg daily • AUC0–12 hr was 170.53 and 225.53 ng · hr/mL on 2 consecutive days 25 Prospective, crossover pharmacokinetics study (n = 5) Patients with ESRD awaiting kidney transplantation receiving sublingual or oral tacrolimus for 3 days Contents of capsule placed under tongue; pt instructed not to swallow for 5 min and not to eat or drink for 15 min Sublingual:oral dosing conversion ratios of 1:2 (with nystatin) and 1:1 (with clotrimazole) 28 Prospective pharmacokinetics study (n = 5) Kidney transplantation candidates, CF pt, and healthy volunteer Contents of capsule placed under tongue; subject instructed not to swallow for 15 min and then to spit and rinse mouth with water Tacrolimus levels almost undetectable when mouth rinsed after sublingual administration 29 Prospective, crossover pharmacokinetics study (n = 6) Liver transplants within the first week after transplantation 1-mg/mL suspension administered under tongue drop by drop over 10 min; pt instructed to avoid swallowing during administration • Variable pharmacokinetic values • No differences in mean trough and AUC with sublingual vs. oral administration. a CF = cystic fibrosis, BCAR = biopsy-confirmed acute rejection, AUC = area under the concentration–time curve, Cmax = maximum concentration, ISHLT = International Society of Heart and Lung Transplantation, ESRD = end-stage renal disease. Open in new tab Clinical experience Early experience with tacrolimus occurred with thoracic organ transplant recipients. The first report of successful sublingual administration included 6 lung transplant recipients with cystic fibrosis.19 During sublingual tacrolimus administration, 46% of tacrolimus trough concentrations were within the therapeutic range (10–17 ng/mL), 28% were supratherapeutic (>17 ng/mL), and 26% were subtherapeutic (<10 ng/mL). These patients were followed for a mean of 3.6 months (range, 1.5–5 months). During that time, six episodes of biopsy-confirmed acute rejection occurred in 5 patients, and four of these cases were associated with tacrolimus concentrations of <5 ng/mL in the preceding seven days. The same investigators retrospectively reviewed an additional 22 patients who received a lung transplant for a variety of indications, and 77% of patients achieved therapeutic or supratherapeutic trough concentrations while receiving sublingual tacrolimus. Only 7 patients were followed for more than 6 months; of these, 43% experienced biopsy-confirmed acute rejection.20 A single-center, retrospective review of 16 hospitalized heart and lung transplant recipients who received sublingual tacrolimus for at least 5 consecutive days was conducted by Collin et al.21 The indication for lung transplantation was cystic fibrosis for the majority of patients. The mean sublingual tacrolimus dose of 0.116 ± 0.096 mg/kg daily corresponded to a mean AUC of 230 ± 74.1 ng · hr/mL (n = 4), while a mean oral dose of 0.414 ± 0.246 mg/kg daily was needed to achieve a similar AUC of 252 ± 92.7 ng · hr/mL (n = 5). The relative exposure of sublingual to oral tacrolimus translates to a dosing conversion ratio of approximately 1:3. The pharmacokinetic profile observed after sublingual administration of tacrolimus was more similar to that of a tacrolimus suspension, with a lower Cmax and a prolonged time to Cmax, suggesting that the total exposure may not be equivalent between sublingual and oral tacrolimus despite achieving similar trough concentrations. During an average follow-up period of only 16 days (range, 5–46 days), no nephrotoxicity, neurotoxicity, or International Society for Heart and Lung Transplantation grade 2 or greater acute rejection22 was observed in patients who received sublingual tacrolimus. However, some patients reported an unpleasant taste with sublingual administration. Watkins and colleagues23 reported a single-center experience with 34 lung transplant recipients whose route of tacrolimus administration was converted from oral to sublingual. Adult patients receiving tacrolimus who achieved steady-state concentrations while using both routes of administration were included. The conversion ratio was calculated using the following equation: (sublingual tacrolimus conc./daily sublingual dose)/(oral tacrolimus conc./daily oral dose). Using this method, the sublingual:oral dose conversion ratio was 0.46 ± 0.20. This ratio was unaffected by the setting in which the transition from one form to another occurred (0.46 ± 0.24 for inpatient versus 0.45 ± 0.13 for outpatient, p = 0.82), presence of impaired gastric emptying (0.49 ± 0.16 with delayed emptying versus 0.42 ± 0.24 without suspected impairment, p = 0.31), or indication for transplantation (0.53 ± 0.15 for cystic fibrosis and scleroderma versus 0.45 ± 0.21 for all others, p = 0.54). Mucosal irritation without ulceration occurred in 1 patient but did not require route conversion. No serious adverse events, including nephrotoxicity and hepatotoxicity, were noted with administration of sublingual tacrolimus. The authors concluded that tacrolimus administration may be safely converted between the sublingual and enteral routes in a predictable fashion. Sublingual tacrolimus has also been used in abdominal organ transplant recipients. Romero and colleagues24 reported the first successful use of sublingual tacrolimus in a kidney transplant recipient. The steady-state AUC0–12 hr measured on consecutive days differed dramatically, suggesting that sublingual absorption is highly variable. Drug-interaction considerations An investigation of five patients with end-stage renal disease awaiting kidney transplantation who were converted from sublingual to oral tacrolimus in the presence and absence of an interacting medication, clotrimazole, was performed by Tsapepas et al.25 Less variation in the dose-normalized AUC0–6 hr occurred when converting patients receiving tacrolimus and clotrimazole (27.2–66.0 and 32.4–76.0 mg · hr/L for sublingual and oral tacrolimus, respectively) compared with those receiving tacrolimus plus nystatin (9.3–63.0 and 4.9–23.3 mg · hr/L for sublingual and oral tacrolimus, respectively). The authors concluded that sublingual dosing of tacrolimus would require an individualized approach and a 1:2 sublingual:oral dose conversion could be used for patients without interacting medications while a 1:1 conversion could be considered for those on concomitant interacting therapy. The presence of both PGP and CYP3A4 and CYP3A5 isoenzymes in the gastrointestinal tract creates the potential for varying magnitudes of drug interactions based on the route of administration, which has been demonstrated in other investigations of nonoral tacrolimus. In a study of 19 kidney transplant recipients, administration of oral ketoconazole with oral tacrolimus resulted in significantly greater exposure compared with coadministration with i.v. tacrolimus, as measured by AUC increases of 109% and 42% from baseline, respectively.26 Similarly, when healthy volunteers received oral rifampin in combination with i.v. and oral tacrolimus, a more profound decrease in tacrolimus bioavailability was observed (14.4 ± 5.7% and 7.0 ± 2.7%, respectively).27 The variable effects of inducers and inhibitors on tacrolimus exposure should be considered when converting between different routes of administration. Administration considerations Because a sublingual formulation is not commercially available for tacrolimus, the most commonly reported method of sublingual tacrolimus administration in the aforementioned studies19–21,23–25 involved placing the contents of capsules under the patient’s tongue, avoiding swallowing for a period of 5–15 minutes and avoiding any oral intake for 15–30 minutes. However, alternative sublingual administration techniques have resulted in findings that make the clinical utility of sublingual tacrolimus less certain. When 18 healthy volunteers were instructed to spit and rinse the mouth with water 15 minutes after sublingual administration of the contents of tacrolimus capsules, 11 did not have detectable blood tacrolimus levels.17 A swallowing event was noted for 3 volunteers with detectable tacrolimus concentrations, with a Cmax of 1.3–22.0 μg/L. The Cmax of those without a swallowing event was 1.3–7.2 μg/L. Of the 18 volunteers, 5 experienced paresthesia at the application site with sublingual administration, and all reported difficulty holding the powder under the tongue without swallowing for the required 15 minutes. In another study of 3 kidney transplant candidates, 1 patient with cystic fibrosis, and 1 healthy volunteer receiving sublingual tacrolimus, very low levels of tacrolimus were observed when this same administration method was applied.28 These observations suggest that a significant portion of sublingual tacrolimus doses may not be readily absorbed in the oral cavity but rather ingested and absorbed enterally. While all of the previous reports described the administration of the contents of tacrolimus capsules, one study used a 1-mg/mL tacrolimus suspension administered drop by drop over a period of 10 minutes.29 Conversion between enteral and sublingual administration of tacrolimus suspension in 6 adult liver transplant recipients resulted in mean trough concentrations and AUCs that did not differ significantly between the two routes (trough concentrations of 11.2 ± 11.3 ng/mL versus 10.4 ± 7.4 ng/mL for enteral and sublingual routes, respectively [p = 0.37], and AUCs of 160.8 ± 115.9 ng · hr/mL versus 181.5 ± 114.1 ng · hr/mL for enteral and sublingual routes, respectively [p = 0.19]). Overall, the pharmacokinetic parameters of tacrolimus were highly variable in this study.29 Tacrolimus is considered a hazardous drug and, if administered in any form other than intact capsules, requires special labeling, handling, and disposal (Table 2).30,31 Due to the potential for environmental contamination, anyone handling open tacrolimus capsules for either direct sublingual administration or compounding should wear two pairs of gloves meeting the American Society for Testing and Materials standards for chemotherapy gloves. In addition, compounding should be performed in a ventilated cabinet, and a gown should also be worn. All healthcare providers, family members, and other caregivers who may participate in sublingual tacrolimus administration, especially women of childbearing potential, should be educated about the risk of reproductive toxicity.30,31 Table 2 Examples of Dispensing, Administration, and Handling Instructions for Sublingual Tacrolimus Medication-Use Phase Instructions   Dispensing Dispense intact capsules of immediate-release tacrolimus. Label includes sublingual administration instructions and need for special handling precautions.   Administration Open the capsules, place the contents of capsules under the pt tongue, and allow to dissolve completely. Avoid swallowing for 5–15 min. Avoid any oral intake for 15–30 min.   Handling When handling open capsules, wear powder-free nitrile gloves. Medication-Use Phase Instructions   Dispensing Dispense intact capsules of immediate-release tacrolimus. Label includes sublingual administration instructions and need for special handling precautions.   Administration Open the capsules, place the contents of capsules under the pt tongue, and allow to dissolve completely. Avoid swallowing for 5–15 min. Avoid any oral intake for 15–30 min.   Handling When handling open capsules, wear powder-free nitrile gloves. Open in new tab Table 2 Examples of Dispensing, Administration, and Handling Instructions for Sublingual Tacrolimus Medication-Use Phase Instructions   Dispensing Dispense intact capsules of immediate-release tacrolimus. Label includes sublingual administration instructions and need for special handling precautions.   Administration Open the capsules, place the contents of capsules under the pt tongue, and allow to dissolve completely. Avoid swallowing for 5–15 min. Avoid any oral intake for 15–30 min.   Handling When handling open capsules, wear powder-free nitrile gloves. Medication-Use Phase Instructions   Dispensing Dispense intact capsules of immediate-release tacrolimus. Label includes sublingual administration instructions and need for special handling precautions.   Administration Open the capsules, place the contents of capsules under the pt tongue, and allow to dissolve completely. Avoid swallowing for 5–15 min. Avoid any oral intake for 15–30 min.   Handling When handling open capsules, wear powder-free nitrile gloves. Open in new tab Discussion The advantages and limitations of various routes of tacrolimus administration are compared in Table 3. Although attractive in many ways, sublingual tacrolimus administration presents several challenges. While some evidence indicates that sublingual administration may be used to achieve therapeutic trough concentrations and provide guidance for dose conversion, transitioning between oral and sublingual tacrolimus dosing will certainly necessitate increased TDM. The toxicities associated with oral tacrolimus may still occur with sublingual administration of the drug. Similar drug interactions also exist with sublingual administration and seem less predictable than those associated with oral administration. Capsule disassembly and sublingual dissolution, particularly in the outpatient setting, may not be the most accurate and reliable method of drug delivery. Poor palatability may present barriers to adherence when tacrolimus is administered sublingually. If handled improperly, open capsules present a risk to the healthcare professional or caregiver administering the drug as well as to those who might encounter the compound through contamination of the surrounding environment. Table 3 Considerations for Selecting Route of Tacrolimus Administration Route Advantages Limitations Oral capsules • Commercially available • Well studied for pharmacokinetics, efficacy, and safety • Trough concentration correlated with exposure • Patients must be able to swallow intact capsules • Variable bioavailability Oral or enteral suspension • Dosing flexibility • May be administered through a variety of enteral accesses without disrupting enteral nutrition • Requires compounding • Special handling precautions • Exposure differs from oral administration despite similar trough concentrations • Poorer correlation between trough concentration and exposure than with oral capsules Intravenous • Commercially available • Eliminates concerns for incomplete or erratic absorption • Can be administered when enteral access is unavailable or contraindicated • Error-prone dose conversion and dilution • Special handling precautions • Must be dispensed in glass or polyethylene containers • Excipient associated with anaphylaxis • Increased risk of toxicity • Must be administered as a continuous infusion Sublingual Offers an alternative to oral, enteral tube, and i.v. administration • Special handling precautions • Erratic absorption, potential for ingestion • Barriers to adherence and proper administration technique • Less predictable drug–drug interactions • Unknown correlation between trough concentration and exposure • Long-term outcomes unknown Route Advantages Limitations Oral capsules • Commercially available • Well studied for pharmacokinetics, efficacy, and safety • Trough concentration correlated with exposure • Patients must be able to swallow intact capsules • Variable bioavailability Oral or enteral suspension • Dosing flexibility • May be administered through a variety of enteral accesses without disrupting enteral nutrition • Requires compounding • Special handling precautions • Exposure differs from oral administration despite similar trough concentrations • Poorer correlation between trough concentration and exposure than with oral capsules Intravenous • Commercially available • Eliminates concerns for incomplete or erratic absorption • Can be administered when enteral access is unavailable or contraindicated • Error-prone dose conversion and dilution • Special handling precautions • Must be dispensed in glass or polyethylene containers • Excipient associated with anaphylaxis • Increased risk of toxicity • Must be administered as a continuous infusion Sublingual Offers an alternative to oral, enteral tube, and i.v. administration • Special handling precautions • Erratic absorption, potential for ingestion • Barriers to adherence and proper administration technique • Less predictable drug–drug interactions • Unknown correlation between trough concentration and exposure • Long-term outcomes unknown Open in new tab Table 3 Considerations for Selecting Route of Tacrolimus Administration Route Advantages Limitations Oral capsules • Commercially available • Well studied for pharmacokinetics, efficacy, and safety • Trough concentration correlated with exposure • Patients must be able to swallow intact capsules • Variable bioavailability Oral or enteral suspension • Dosing flexibility • May be administered through a variety of enteral accesses without disrupting enteral nutrition • Requires compounding • Special handling precautions • Exposure differs from oral administration despite similar trough concentrations • Poorer correlation between trough concentration and exposure than with oral capsules Intravenous • Commercially available • Eliminates concerns for incomplete or erratic absorption • Can be administered when enteral access is unavailable or contraindicated • Error-prone dose conversion and dilution • Special handling precautions • Must be dispensed in glass or polyethylene containers • Excipient associated with anaphylaxis • Increased risk of toxicity • Must be administered as a continuous infusion Sublingual Offers an alternative to oral, enteral tube, and i.v. administration • Special handling precautions • Erratic absorption, potential for ingestion • Barriers to adherence and proper administration technique • Less predictable drug–drug interactions • Unknown correlation between trough concentration and exposure • Long-term outcomes unknown Route Advantages Limitations Oral capsules • Commercially available • Well studied for pharmacokinetics, efficacy, and safety • Trough concentration correlated with exposure • Patients must be able to swallow intact capsules • Variable bioavailability Oral or enteral suspension • Dosing flexibility • May be administered through a variety of enteral accesses without disrupting enteral nutrition • Requires compounding • Special handling precautions • Exposure differs from oral administration despite similar trough concentrations • Poorer correlation between trough concentration and exposure than with oral capsules Intravenous • Commercially available • Eliminates concerns for incomplete or erratic absorption • Can be administered when enteral access is unavailable or contraindicated • Error-prone dose conversion and dilution • Special handling precautions • Must be dispensed in glass or polyethylene containers • Excipient associated with anaphylaxis • Increased risk of toxicity • Must be administered as a continuous infusion Sublingual Offers an alternative to oral, enteral tube, and i.v. administration • Special handling precautions • Erratic absorption, potential for ingestion • Barriers to adherence and proper administration technique • Less predictable drug–drug interactions • Unknown correlation between trough concentration and exposure • Long-term outcomes unknown Open in new tab The studies that examined the sublingual administration of tacrolimus had several limitations. The majority were retrospective, not comparative, in nature and reflected individual center experiences with small numbers of patients. When reported, outcomes addressing rejection and toxicities were noted during brief follow-up periods, thereby preventing any conclusions regarding long-term safety and efficacy. The largest cohort of lung transplant recipients did not include mechanically ventilated patients, a likely target population for sublingual tacrolimus administration.23 In addition to variations in dosage forms, the method of administration differed significantly among the studies. The variability and absence of any differences between oral and sublingual tacrolimus when a suspension was used suggest that the same dosing conversion cannot be applied to this formulation. Few endpoints related to patient preference, adherence, or quality of life were evaluated. Most importantly, none of these investigations evaluated the correlation between trough concentration and drug exposure. It remains unknown whether achieving trough concentrations comparable to those achieved with oral administration actually provides equivalent tacrolimus exposure or if alternative trough target levels are necessary when administering tacrolimus sublingually. This uncertainty may significantly limit the utility of sublingual administration, particularly in the immediate posttransplantation period when adequate tacrolimus exposure is crucial.20, 32, 33 Multiple alternative approaches to oral tacrolimus administration are currently available, but none are as safe, well-studied, and correlated to total exposure as traditional oral tacrolimus capsules. Therefore, any alternative method selected should be considered a temporary substitution and used for the minimal duration possible. If enteral access is available and use of the gastrointestinal tract is not contraindicated, administration of tacrolimus suspension is favored. This route is not associated with an increased risk of toxicity and, though not identical, is likely most similar to the use of oral capsules. When dosed, prepared, administered, and monitored properly, i.v. tacrolimus is a reliable method of administration for patients who cannot receive enteral medication. The evidence available for buccal or rectal administration is not sufficient to provide recommendations for these routes. Sublingual administration offers an alternative to enteral and i.v. tacrolimus. Experience with this route of administration is accumulating, but a standardized approach for dose conversion, administration, and TDM has not been well established. The published clinical experience suggests that tacrolimus capsules provide the most consistent formulation for sublingual administration. When converting from oral to sublingual tacrolimus capsules, 50% of the current or anticipated oral dose should be administered and serum drug levels monitored frequently until therapeutic steady-state trough levels are achieved. For patients who are not on a stable oral dose and those receiving medications interacting at the intestinal level, dose conversion will require individualization. Pharmacy-dispensed doses of sublingual tacrolimus must indicate the instructions for administration technique and the need for special handling precautions on the label. Other strategies such as healthcare provider education and nursing instructions visible on the medication administration record should be implemented to ensure that these precautions are observed for doses retrieved from an automated dispensing cabinet. Conclusion In addition to enteral tube and i.v. tacrolimus dosing, sublingual administration may be considered for short-term use in patients who are unable to receive medications orally. Based on the available data, it is reasonable to initiate sublingual tacrolimus at 50% of the current or anticipated oral dose in the absence of interacting medications. Dosing must be individualized, taking into consideration concomitant interacting medications, and adjusted to target levels based on TDM. Footnotes The authors have declared no potential conflicts of interest. The Clinical Consultation section features articles that provide brief advice on how to handle specific drug therapy problems. All articles are based on a systematic review of the literature. The assistance of ASHP’s Section of Clinical Specialists and Scientists in soliciting Clinical Consultation submissions is acknowledged. Unsolicited submissions are also welcome. References 1 Scientific Registry of Transplant Recipients . 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TI - Sublingual tacrolimus as an alternative to oral administration for solid organ transplant recipients
JO - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp140322
DA - 2015-02-15
UR - https://www.deepdyve.com/lp/oxford-university-press/sublingual-tacrolimus-as-an-alternative-to-oral-administration-for-cNvkdEnmPs
SP - 277
VL - 72
IS - 4
DP - DeepDyve
ER -