Objectives: Early posttransplant, the administration of oral or enteral medications in pancreas transplant is challenging because of the management of postoperative ileus and gastroparesis. The use of sublingual tacrolimus may offer a promising alternative. The objective of this study was to compare the pharmacokinetics and perioperative outcomes between oral and sublingual tacrolimus in pancreas transplant. Materials and Methods: This was a single-center, retrospective study of pancreas transplants between January 1, 2011, and July 1, 2018. We transitioned our tacrolimus protocol from oral to sublingual dosing in pancreas transplant patients beginning January 1, 2017. Results: This analysis included 54 pancreas transplant recipients, with 17 patients on sublingual tacrolimus matched to 37 patients on oral tacrolimus. Within the sublingual group, it took a mean of 3.2 days to achieve a therapeutic tacrolimus trough level (?8 ng/mL) compared with a mean of 3.8 days in the oral group (P = .175). There was no difference in the incidence of hyperkalemia and supratherapeutic tacrolimus levels between groups. The conversion factor from sublingual to oral in this patient population was 0.67, which was different than what has been reported in other populations. Clinical outcomes were similar between groups.Conclusions: Sublingual tacrolimus use in pancreas transplant patients appears to be a safe and effective strategy to avoid oral or intravenous therapy in the perioperative period and may reduce the time to achieve therapeutic levels.
Key words : Clinical outcomes, Enteral administration, Methods of dose administration
As of 2020, there were 2605 newly activated patients on the pancreas transplant (PTX) wait list in the United States and over 1000 PTX have been performed.1 Postoperative ileus is a frequent complication after abdominal surgeries, including PTX. During this period of impaired gastric motility, nasogastric tubes are often placed to decompress the bowel and dietary restrictions are enforced until the patient has return of normal bowel function.2 Concerns for malabsorption can affect postoperative medication management, namely, the administration of oral medications. Alternative routes of administration, including intravenous and sublingual, are typically used. Sublingual administration allows medications to be absorbed directly from the oral cavity and is less invasive than intravenous therapy. Sublingual administration of medications could be beneficial for PTX recipients with potential malabsorption issues.3
To date, there are no studies assessing the use of sublingual tacrolimus in PTX recipients. A majority of the literature supporting its use is in cardiothoracic transplant recipients. In a retrospective study, Reams and colleagues4 assessed whether it was safe and efficacious to administer sublingual tacrolimus as an alternative to intravenous administration in heart and lung transplant recipients. They found that patients achieved therapeutic drug levels 53% of the time with no major adverse events. However, no pharmacokinetic analysis, including necessary dosing conversion from sublingual to oral administration of tacrolimus was completed.4 Another study by Watkins and colleagues aimed to identify the conversion ratio from sublingual to oral administration of tacrolimus that would best achieve steady-state therapeutic concentrations in lung transplant recipients. The study found the ratio to be 0.46 to 0.26 for oral versus sublingual, thus concluding the required sublingual tacrolimus dose is approximately half of the oral dose.5
Beginning January 1, 2017, our institution’s tacrolimus protocol in simultaneous kidney-pancreas and solitary pancreas transplants was updated to reflect the preferential use of sublingual tacrolimus over the suspension formulation in the immediate postoperative period to optimize absorption. The objective of this study was to compare the clinical, pharmacokinetic, and perioperative outcomes between oral and sublingual tacrolimus administration in PTX recipients.
Materials and Methods
This was a single-center, retrospective study that included adults who underwent PTX (solitary pancreas transplants, simultaneous kidney-pancreas transplants, and pancreas-after-kidney transplants) between January 1, 2011 and August 31, 2018. Beginning in 2017, our institution started using sublingual tacrolimus in PTX. Initial dosing was subject to provider preference with a goal tacrolimus trough level of 8 to 12 ng/dL. Patients were continued on sublingual tacrolimus until the nasogastric tube was removed, often within 48 to 72 hours posttransplant. At that time, patients were converted to oral tacrolimus using a 1:2 sublingual-to-oral conversion ratio. Pharmacokinetic outcomes assessed included days to therapeutic tacrolimus level (?8 ng/dL), number of subtherapeutic tacrolimus levels within 30 days, proportion of therapeutic tacrolimus levels (8-12 ng/dL) within 30 days, proportion of supratherapeutic tacrolimus levels within 30 days (>15 ng/dL), and mean tacrolimus dose and level at days 3, 7, 14, and 30 posttransplant. Conversion ratio of sublingual-to-oral dosing was also calculated using the formula (sublingual blood concentrations/sublingual daily dose)/(oral blood concentrations /oral daily dose). Clinical outcomes assessed included incidence of hyperkalemia, defined as a potassium ?6 mEq/L, and biopsy-proven kidney and/or pancreas rejection.
Unmatched cohorts (oral vs sublingual groups) had significantly different characteristics. We performed propensity score matching to create similar cohorts for comparison. We used the greedy nearest neighbor without replacement approach. We completed a 1-to-2 match (sublingual to oral), with the maximum caliper set at 0.3. We matched on the following characteristics: age, race, sex, transplant type (simultaneous pancreas transplants vs solitary pancreas transplants or pancreas-after-kidney transplants), and rabbit antithymocyte globulin induction therapy. We used the standardized mean differences method to compare cohorts’ characteristics before and after the match. Mean or median values were used for continuous or ordinal variables, whereas percentages were used for categorical data. Standard univariate statistics were used to compare matched groups, including the chi-square test for nominal data, the t test for continuous data, or the Mann-Whitney U test for nonnormally distributed data. Kaplan-Meier survival curves were produced to compare time to acute rejection or censoring, with the log-rank test used to determine statistical significance. The threshold for statistical significance was set as a 2-sided value of P < .05. All analyses were performed with SPSS software (version 23.0, IBM).
A total of 54 PTX recipients were included in the analysis, with 17 patients who received sublingual tacrolimus matched to 37 patients who received standard oral tacrolimus. The propensity score matching was successful, as baseline characteristics were similar between groups (Table 1). The mean age at transplant for both groups was 42 years, and most patients received induction with antithymocyte globulin.
Table 2 displays the clinical pharmacokinetics of tacrolimus, as well as clinical outcomes. Within the sublingual group, it took a mean of 3.2 days to achieve a therapeutic tacrolimus trough level compared with a mean of 3.8 days in the oral tacrolimus group (P = .175). There was no difference in the incidence of supratherapeutic tacrolimus levels between groups. The proportion of tacrolimus trough levels within range (8-12 ng/dL) was slightly higher in the sublingual group (0.72 ± 0.16) compared with those in the oral group (0.69 ± 0.12); however, this did not reach significance. Of note, the conversion factor from sublingual to oral tacrolimus in this patient population was 0.67. Clinical outcomes included rates of hyperkalemia and rejection, which were also similar between groups.
Our study is the first to investigate the conversion ratios for sublingual tacrolimus and oral tacrolimus in PTX. This study demonstrated that a conversion factor of 0.67 can be used for transition from sublingual to oral tacrolimus to achieve similar trough levels. The results of this study provide a reference point for clinicians who use sublingual tacrolimus in PTX. The results also demonstrated that the use of sublingual tacrolimus in PTX is safe and effective to achieve therapeutic trough concentrations rapidly after transplant. The use of sublingual tacrolimus reduced the time to achieve therapeutic levels by nearly a day, compared with an oral tacrolimus-based therapy.
This use of sublingual tacrolimus in the PTX population has not been previously studied. Our single-center data are unique compared with other studies that were primarily conducted to determine appropriate conversion between sublingual and oral tacrolimus formulations. A pilot study performed by Tsapepas and colleagues used a crossover design to evaluate the pharmacokinetic parameters of sublingual and oral tacrolimus administration in 6 patients with end-stage renal disease.6 They also investigated the effect of concurrent clotrimazole at 10 mg twice daily and nystatin at 5 mL twice daily. Each group of patients received 5 sublingual doses of tacrolimus followed by a 2-day washout period and 5 doses of oral tacrolimus. Researchers found a 1:1 sublingual-to-oral conversion ratio with concurrent clotrimazole therapy compared with a 1:2 conversion in the absence of interacting agents.6 In the liver transplant population, Nasiri-Toosi and colleagues7 performed a crossover pilot study that evaluated pharmacokinetic parameters of sublingual and oral tacrolimus administration at steady state and found no significant differences between oral and sublingual tacrolimus in regard to trough concentration, time of peak concentration, or the area under the curve (AUC). They found the mean ratio of sublingual-to-oral tacrolimus AUC to be 0.89 ± 0.41. Their study showed similar pharmacokinetic properties and bioavailability of sublingual and oral tacrolimus, which suggested a 1:1 sublingual-to-oral dose ratio.7 These prospective studies demonstrated that sublingual tacrolimus is a viable option when oral administration is not feasible; however, both are limited by their small sample size.6,7
There have been a series of retrospective studies that evaluated dose ratios for sublingual-to-oral conversion of tacrolimus. Collin and colleagues described their inpatient use of sublingual tacrolimus in 16 cardiothoracic transplant recipients (13 lung recipients and 3 heart recipients).8 The average dose of sublingual tacrolimus was 0.08 mg/kg/d, and 90.4% of recipients had trough levels that were within a predefined therapeutic range. The pharmacokinetic analyses were only completed on the lung transplant recipients. Mean values for AUC were similar between the sublingual doses of 0.116 ± 0.096 mg/kg and oral doses of 0.414 ± 2.46 mg/kg, and the authors concluded a 4-fold lower dose of sublingual tacrolimus was needed. Therefore, the dose conversion would be 1:4 for sublingual versus oral administration.
Although the beneficial crossover design allowed patients to serve as their own comparators, the small sample size was a limitation.8 Doligalski and colleagues created a 10-question online survey to assess the current state of sublingual tacrolimus and distributed this survey to pharmacists at transplant centers that performed more than 100 transplants in 2013. The survey was completed by 59 of the 90 (65.5%) transplant centers. Sublingual administration was largely used in the lung transplant population (67.5%); however, it was used in all other organs as well. The most common dose conversion was 1:2 for sublingual versus oral. Overall, the authors concluded that most centers surveyed felt that sublingual tacrolimus was an alternative option when oral administration is not feasible.9
This is the first report to evaluate the pharmacokinetic and clinical outcomes of the use of sublingual tacrolimus in PTX. Limitations of this study included a small sample size and retrospective design. Additionally, the initial regimen was provider specific. Time to therapeutic range may have been affected in patients who received a more conservative start dose.
Overall, this study demonstrated that the use of sublingual tacrolimus in PTX appears to be a safe and effective strategy to avoid oral or intravenous therapy in the perioperative period and may reduce the time needed to achieve therapeutic levels. No difference in rates of adverse effects of incidence of rejection was observed between groups. Larger prospective clinical trials are warranted to further investigate the effects of sublingual tacrolimus on clinical outcomes compared with oral formulations.
Volume : 19
Issue : 6
Pages : 592 - 595
DOI : 10.6002/ect.2020.0391
From the 1Department of Pharmacy Services, Medical University of South Carolina, Charleston; the 2Department of Surgery, Medical University of South Carolina, Charleston; and the 3Department of Pharmacy, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina, USA
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Neha Patel, Solid Organ Transplant, Medical University of South Carolina, 150 Ashley Avenue, MSC 584, Charleston, SC 29425, USA
Table 1. Baseline Characteristics
Table 2. Clinical Pharmacokinetics of Tacrolimus and Clinical Outcomes