Use of Sublingual Tacrolimus in Adult Blood and Marrow Transplant Patients: a Pilot Study
Phase: PHASE4
Conditions: Immunosuppression, Stem Cell Transplant, Bone Marrow Transplant
Sponsor: Mayo Clinic

 
 
Use of sublingual tacrolimus in adult blood and 
marrow transplant patients: a pilot study 
 
 
NCT# NCT04041219 
 
16-MAY-2019 

 
 
Department of Pharmacy 
Research Proposal 
 
 
Use of sublingual tacrolimus in adult blood and 
marrow transplant patients: a pilot study 
 
 
 
Principal Investigator 
 
Heather A. Personett, PharmD 
 
Co-Investigators 
 
Robert C. Wolf, PharmD 
Hassan B. Alkhateeb, MD 
 
 
 
Protocol Version: 2.0 
Protocol Version Date: 16-May-2019 
 

Abstract 
Barriers to oral (PO) tacrolimus in recipients of an allogeneic blood or marrow transplant 
(BMT) are not uncommon and often result in reliance on intravenous (IV) tacrolimus, a 
formulation which is fraught with concerns. Sublingual (SL) administration of tacrolimus 
is widely used as a safe and effective alternative in the solid organ transplant population. 
Similar benefits may be appreciated by patients undergoing BMT, including avoidance of 
risks and expense associated with IV tacrolimus, as well as reduced pill burden and 
limited trough variability relative to PO tacrolimus. This study will establish feasibility and 
gather preliminary data on the dose conversion ratio of PO to SL tacrolimus through 
comparison of trough concentrations drawn during PO and SL tacrolimus delivery during 
routine laboratory monitoring. Results will be used to inform future studies in larger 
cohorts and assist in determining an accurate conversion ratio, which is imperative to 
inform clinician decision-making and allow for prescription of doses which result in 
trough levels that ensure the safety and efficacy of tacrolimus.  
 
Specific Aims 
1) Demonstrate feasibility of SL administration of tacrolimus in blood and marrow 
transplant (BMT) patients 
2) Gather preliminary data to determine the conversion ratio of oral (PO) to 
sublingual (SL) administration of tacrolimus needed to achieve equivalent whole 
blood concentrations in BMT patients  
 
Background and Significance 
Tacrolimus is a calcineurin inhibitor frequently used in the prevention of graft-versus-host 
disease (GVHD) in recipients of an allogeneic blood or marrow transplant (BMT).(1–5) 
Unfortunately, barriers to oral (PO) medication administration are not uncommon in this 
population and include severe mucositis, dysphagia, altered mental status, intubation 
without oral access and high-output diarrhea. In such cases, clinicians are often forced 
to rely on intravenous (IV) administration of tacrolimus, a formulation which is fraught 
with concerns. Studies describe higher rates of nephrotoxicity and neurotoxicity with IV 
compared to PO tacrolimus and reports of life-threatening cardiac arrhythmias and 
anaphylaxis to the castor oil component exist.(6–9) An alarmingly high rate of PO to IV 
dose calculation errors has been described, likely due in part to inconsistent reports of 
dose conversion ratios.(10) Additionally, dilution of the concentrated IV product to the 
appropriate dose is challenging and administration requires extended infusion times of 
12 to 24 hours to minimize fluctuations of blood levels. This can complicate 
administration of other medications in patients with limited IV access and also result in 
erroneous reporting of blood concentrations, should blood for assay be taken from the 
line in which tacrolimus is being infused.  The IV product is also more costly than other 
formulations and thus increases healthcare expenses for institutions and patients 
alike.(11,12) At Mayo Clinic, the institutional cost of doses <5 mg is $330 per day, 
compared to $0.98 per 1 mg oral capsule.  It is for these reasons an alternative to IV 
tacrolimus administration is desirable.  
 
Sublingual (SL) administration of tacrolimus is widely used as a safe and effective 
alternative to the IV product in the solid organ transplant (SOT) population.(12–17) It has 
been adopted routinely in the heart, lung and abdominal solid organ transplant practices 
at Mayo Clinic in Rochester. More recently it has been used successfully in the 
prevention of GVHD in pediatric transplant patients.(18) Tacrolimus can be administered 
sublingually by opening a capsule and placing the contents under the tongue, with 
patients instructed not to swallow until after dissolution occurs and avoid eating, drinking 

or suctioning of secretions for the subsequent 15 to 30 minutes.(10–12,14,16,18,19) 
Patients were able to achieve goal trough levels using SL tacrolimus with minimal, if any, 
reported adverse effects. Published literature indicates the area under the blood-
concentration-time curve (AUC) for SL tacrolimus is well correlated with whole blood 
trough levels, the current standard of care for therapeutic drug monitoring and guidance 
of dose adjustments to maintain concentrations within the desired therapeutic 
window.(11,12) In addition to serving as a safe and effective alternative to IV 
administration in patients who become intolerant of oral medications, the SL formulation 
offers advantages over PO tacrolimus as well. When administered orally, tacrolimus has 
poor bioavailability (approximately 25%) due to extensive first-pass metabolism and P-
glycoprotein efflux.(20) These concerns are mitigated with SL administration, which 
allows for direct absorption into the blood. Avoidance of first-pass metabolism may also 
minimize the degree of interaction between tacrolimus and drugs that effect hepatic 
cytokine P-450 enzymes.(18) Reduced doses with SL administration can also decreased 
pill burden and cost associated with tacrolimus use.(12,15,16) Studies undertaken to 
determine the optimal SL to PO dose conversion ratio in SOT patients report slightly 
variable results depending on the type of organ received,(10–12,14,16) with most 
centers recommending a ratio of 1:1 or 1:2.(17) Given that enteral and first-pass hepatic 
metabolism are bypassed with the SL route, one report suggests that a ratio of 1:1 be 
used when major drug interactions are present.(14) 
 
While the volume of data surrounding SL tacrolimus is growing in SOT, published 
reports describing its use in BMT are extremely limited and entirely lacking in an adult 
BMT population. Determination of the feasibility of administration and pharmacokinetic 
parameters in this cohort is an essential exploratory step toward establishing SL 
administration as an alternative to IV tacrolimus for patients undergoing BMT who are 
unable to tolerate the PO formulation. The purpose of this study will be to gather 
preliminary data related to feasibility and dose conversion with SL administration in 
clinically stable adult BMT patients. Results will be used to in future studies evaluating 
use of SL tacrolimus in peri-transplant and hospital settings, where IV tacrolimus is used 
in patients intolerant of PO tacrolimus. Determining an accurate conversion ratio is 
imperative to inform clinician decision-making and allow for prescription of doses that 
result in trough levels which ensure both safety and efficacy.  
 
Preliminary Studies 
Prior studies using SL tacrolimus in the SOT population have been conducted in patients 
with varying degrees of illness and in numerous settings. They investigate both transient 
and long-term use SL tacrolimus in the inpatient and outpatient environment. These 
demonstrate patients are able to achieve goal trough levels using SL tacrolimus with 
limited adverse effects, which are confined to adverse taste. The SL formulation shows 
excellent bioavailability due to direct absorption into the bloodstream and an AUC that is 
well correlated with whole blood trough levels. To date there is a single 5-patient case 
series describing SL tacrolimus use to achieve safe and effective trough concentrations 
in pediatric BMT patients. Doses ranged from 0.025-0.078 mg/kg/day in divided doses. 
 
Research Design and Methods 
Overview 
This is a prospective, single-center, crossover, pilot study of consecutive patients 
undergoing allogeneic blood or marrow transplantation (BMT) at Mayo Clinic in 
Rochester Minnesota. It will include adult (age ≥18 years) patients prescribed tacrolimus 
for treatment or prevention of graft-versus-host disease (GVHD) who transition between 

orally administered tacrolimus and the sublingual (SL) route of administration. We will 
report feasibility of the SL formulation in the population and preliminary data on the 
SL:PO dose conversion ratio.  
 
Setting 
This study will be conducted in Rochester, Minnesota, where Mayo Clinic completes 
over 700 blood or marrow transplants per year, approximately 20% of which are 
allogeneic transplants. Around half of these will receive tacrolimus for GVHD prevention. 
As a referral center, patients are diverse with respect to diagnosis and demographics. 
Comprehensive care is provided by a multidisciplinary treatment team including 
physicians from a variety of medical specialties, advanced practice providers, 
pharmacists, nurses, dieticians, care coordinators and social workers. Integrated 
inpatient and outpatient care allows for close monitoring of patients throughout the care 
continuum, with near-daily appointments and twice weekly tacrolimus laboratory 
monitoring conducted locally through day +30 following transplant or longer, as dictated 
by a patient’s medical course.  
 
Identification of Study Subjects 
Individuals will be identified from within the adult allogeneic BMT program at Mayo Clinic 
in Rochester, Minnesota. Participants will include adults prescribed tacrolimus for 
treatment or prevention of GVHD. Vulnerable populations, patients with contraindications 
to tacrolimus, inclusive of hypersensitivity, history of posterior reversible encephalopathy 
syndrome or calcineurin-inhibitor induced thrombotic microangiopathy, and those lacking 
the capacity to consent in English and declining to participate in research will be 
excluded.  
 
Patients will be screened when scheduled for their pre-transplant pharmacist visit. Those 
meeting inclusion and exclusion criteria will be enrolled during a regularly scheduled pre-
transplant clinic appointment. Here they will be supplied with HIPAA Authorization and 
consent forms. The consent form will describe the purpose of the study, the procedures 
to be followed, and the risks and benefits of participation. A copy will be given to each 
participant and this fact will be documented in the participant’s record. Fifteen minutes, 
or additional time as necessary, will be allowed for discussion and patient questions. 
Patients will be informed their care will not be impacted by declining to participate in the 
study.  
 
Definitions 
 
Dose-adjusted conversion ratio of SL and PO tacrolimus (16): 
 
Calculated using the concentration-to-dose ratios for each route of administration 
 
[(Blood concentrationSL/daily doseSL)/(Blood concentrationPO/daily dosePO)] 
 
Steady state trough: obtained following stable/unchanged dosing for a minimum of 4 
dosing intervals (ie, prior to the 5th scheduled dose at the earliest) 
 
Major drug interactions with tacrolimus, ie strong CYP3A4 inhibitors and inducers 
 
Inhibitors: azole antifungals, macrolide antibiotics, protease inhibitors (ex. 
ritonavir, boceprevir) and  
 
Inducers: antimycobacterials (ex. rifabutin, rifampin), anticonvulsants (phenytoin, 
carbamazepine and phenobarbital) 

 
Data including new start or dose changes made in the 7 days preceding a steady 
state trough level for either route of administration will be collected for purposes 
of a secondary analysis 
 
Hepatic dysfunction: liver function tests (AST or ALT) >3x the upper limit of normal or 
any stage of cirrhosis documented as part of the patient’s electronic health record 
(EHR). 
 
Study Procedure 
Enrolled patients will enter the study at their pre-transplant clinic appointment in the 
outpatient setting, with tacrolimus started at day -3 prior to transplant. Prescribers will 
issue a prescription for tacrolimus in the usual way and the recommended starting dose 
will be in accordance with the established protocol (0.04 mg/kg/dose of ideal body 
weight), initially administered sublingually. In accordance with current protocols and 
standards of care, additional dose adjustments may be made at the discretion of the 
treating provider or consulting pharmacist based on their clinical assessments. A 
pharmacist or member of the investigative team will provide consultation to assist with 
this process. At this time the patient will also be provided with a drug diary for recording 
the dose (in milligrams), time, and route of administration for each dose taken.  
 
Around allogeneic transplant, as standard of care patients are maintained on tacrolimus 
with therapeutic drug monitoring performed through collection of whole blood trough 
levels a minimum of twice weekly, or at steady state after a dose change, to ensure 
concentrations are within the desired therapeutic window. For the purposes of this study, 
enrolled patients will begin administering their existing tacrolimus capsules sublingually. 
Patients and caregivers will be educated to open the capsules and place the entire 
contents under the patient’s tongue. Patients will be instructed not to swallow until 
absorption is complete (typically within 1-2 minutes) and avoid eating and drinking 15 
minutes following administration. Doses should be given at 12-hour intervals. Patients 
and caregivers will be instructed to record the day, time and route of each dose in a drug 
diary for review by providers or pharmacists at subsequent clinic visits (Appendix A). 
 
The dose titration and monitoring process will not deviate from usual care in this setting. 
Determination of goal trough level and dose changes will be at the discretion of the 
treating provider and not influenced by this study. Trough levels will be drawn Mondays 
and Thursdays, or at steady state after a dose change, as a component of routine lab 
monitoring. This is consistent with standard of care and usual post-transplant procedure, 
meaning no additional blood samples will be required for completion of this research. 
Should a sub- or supra-therapeutic trough be discovered in advance of this and the 
tacrolimus dose adjusted, 4 dosing intervals will be required on the new dose before a 
trough concentration will be used in study analysis. The same is true if a dose is withheld 
or missed in accordance with provider instructions or patient report. At each patient 
encounter, the provider seeing the patient will inquire about potential barriers to SL 
administration and record patient responses on a study data collection form (Appendix 
B), as well as review the patient’s drug diary for any missed doses. Both the data 
collection form and drug diary will be scanned into the patient’s EHR. Should the patient 
not provide their drug diary at the time of the clinic visit, a detailed history will be 
recorded by the provider and assessed for compliance. Only trough levels drawn during 
periods of full compliance will be used for study purposes. Study personnel will be 
available via pager to assist providers with dose adjustments based on lab results as 
they become available and changes will be communicated to patients in the usual 

manner, either by phone or through the patient online portal. Study personnel will also 
be available as a resource for patients or providers during appointments if needed. 
Patients are instructed to contact a provider via a 24-hour phone line or through the 
online patient portal in the event of questions or concerns.  
 
Cross-over to orally administered tacrolimus can occur immediately after a steady-state 
trough has been obtained on the initial dosage form, or as dictated by the patient’s 
clinical status and ability to tolerate the alternative route of administration. Doses may be 
chosen based on provider discretion in light of drug interactions, clinical status and initial 
trough information. A subsequent tacrolimus trough will be obtained on PO tacrolimus in 
the same manner in which it was measured during the 1st phase, after which point the 
study period will conclude. 
 
Data Collection 
 
Demographics including age, gender, underlying hematologic diagnosis, type of 
allogeneic transplant (related, unrelated, or cord blood) and source (peripheral blood or 
bone marrow) will be collected from the EHR. Conditioning regimen, existing drug 
interactions, comprehensive GVHD prophylaxis strategy, diagnosis of hepatic 
dysfunction, and date of transplant will be reported. The new introduction or dose 
change of a medication with major interaction with tacrolimus (see “Definitions” above) 
within the 7 days prior to study entry or during enrolled will be noted. 
 
Daily tacrolimus dose, reasons for withholding (if applicable), and patient-reported 
barriers to SL administration will be recorded. Trough levels for each route of 
administration will be collected after at least 4 consecutive doses for determination of the 
SL to PO conversion ratio. 
 
Outcomes and Analysis 
 
The primary endpoint is documentation of feasibility of SL tacrolimus administration in 
BMT patients. The secondary endpoint will be to determine the conversion ratio of 
SL:PO administration of tacrolimus, normalized for dose. Descriptive statistics will be 
reported related to remaining data including existing drug interactions and 
comprehensive GVHD prophylaxis strategy. 
 
Patient report of barriers to administration of SL tacrolimus will be used to investigate 
feasibility of the SL formulation. These could include poor tolerability of the SL route, 
lack of understanding related to the administration instructions, or inability to refrain from 
eating or drinking for the defined amount of time. As described in “Study Procedure”, 
these will be recorded at each clinic appointment when the patient sees a provider 
during the study timeframe.  Per-protocol analysis will be conducted to determine the 
conversion ratio of SL and PO administration. Median dose conversion ratios will be 
compared between patients with new major drug interactions or undergoing dose 
changes of these medications and the remainder of the cohort. 
 
We aim to include a total of 10 patients for analysis. This represents approximately 10% 
of the number needed to determine in future study the true conversion ratio with a 10% 
margin of error (n = 97 patients), assuming an estimated conversion ratio of 0.5 
(extrapolated from available literature in the SOT population). Continuous data will be 
described using median (IQR). The conversion ratio of SL:PO administration of 

tacrolimus will be calculated as described above for each patient (note that this is 
adjusted for the daily dose administered). Each subject will serve as his or her own 
control. The median will be determined for the cohort and by subgroup, as described in 
the paragraph above.  
 
Data Storage 
Data will be extracted from the EHR by select study personnel and stored in a password-
protected Research Electronic Data Capture (REDCap) database. This platform meets 
the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA) compliance, with password protection and the ability to assign access levels 
that ensure tightly regulated data sharing. All source data will be de-identified so that 
only a unique study number bearing no relationship to personal identifiers will be used to 
identify participants. Only the investigators involved in the collection and analysis of the 
data will have access to information with individually identifiable private information 
about the human subjects. Reported data will be de-identified and presented only in 
composite form. 
 
Potential Risks and Benefits to Patients 
Potential risks to study participants are minimal and comparable to those of PO 
tacrolimus. Sublingual administration specifically has been well-tolerated in numerous 
reports with limited to no side effects. Reports are inclusive of a wide variety of patient 
populations, such as adult and pediatric patients and in lung, liver, kidney and blood and 
marrow transplant settings. At present, no study reports a serious side effect related to 
SL tacrolimus use and outcomes do not suggest risks for any adverse effects are 
elevated when comparing SL to PO tacrolimus. Possible unique side effects include 
metallic or bitter taste of the medication. Serum trough levels may fluctuate within or 
outside of the therapeutic window when switching between SL and PO formulations, but 
are monitored closely. Similar fluctuations can also occur as a part of routine treatment 
with PO tacrolimus due to changing clinical status, interacting medications or dietary 
intake. Risks in the acute care setting associated with tacrolimus use via any route 
include peripheral edema, pruritus, constipation, diarrhea, nausea, vomiting, anemia, 
changes in leukocyte count, thrombocytopenia, headache, tremor, paresthesia, and 
increased serum creatinine. More serious yet uncommon adverse events include liver 
and renal toxicity, posterior reversible encephalopathy syndrome, infection, seizure, or 
hemolytic uremia syndrome. No additional risk for these adverse events is conferred with 
the use of SL tacrolimus (relative to oral) based on the available literature. Additionally, 
numerous data demonstrate the safe and effective use of tacrolimus in blood and 
marrow transplant for GVHD. It remains a cornerstone of internationally ratified 
guidelines as well as Mayo Clinic clinical practice. Patients will be closely monitored by a 
multidisciplinary medical team, who are well-educated on the risks, as part of the 
standard of care procedures. Other risks associated with blood and marrow transplant 
exist and are expected but will not be captured as a part of this research. No additional 
clinic visits, blood sampling, or medication will be required for completion of this study, 
thus no cost is associated with the transition to SL tacrolimus.  
 
Potential benefits to study participants include reduced in pill burden and decreased 
intra-patient variability of trough levels, due to the ability of SL administration to bypass 
first-pass hepatic metabolism and drug efflux from the P-glycoprotein in the intestine. 
Significant scientific gains may be appreciated through demonstration of feasibility for 
this route of medication delivery. Initial data will illuminate a PO to SL conversion ratio 
which can be tested in a larger cohort of outpatients and extrapolated to environments in 

which IV tacrolimus is currently used, most notably the peri-transplant period and 
inpatient environment. Determination of this ratio will improve clinicians’ ability to 
prescribe doses that result in trough levels that ensure safety and efficacy when 
transitioning patients to SL tacrolimus.  
 
Data Safety and Monitoring 
The principal investigator (PI) or designated co-investigator will ensure screening was 
compatible with inclusion and exclusion criteria and confirm documentation of informed 
consent within 24 hours of patient enrollment. The PI or designated co-investigator will 
be informed of concerns by providers directing patient care as they occur and review 
records within 24 hours of notification. The PI will be responsible for ensuring 
participants’ safety on a daily basis. This includes assuring routine trough monitoring for 
safety and efficacy is performed, weekly review of new records for potential adverse 
events related to SL administration of tacrolimus and reporting of serious adverse events 
and unanticipated problems to the Institutional Review Board (IRB).  
 

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Appendix B 
 
Feasibility Data Collection Form 
 
Transcript for provider questions to patient: 
 
1. Have you experienced any difficulties taking your tacrolimus “under the tongue”? 
a. If yes, what has been the barrier (ex. poor taste, inability to eat or drink, 
slow dissolution of the drug, did not understand the directions)? 
2. Have you missed any tacrolimus doses since your last conversation with a care 
provider?  
a. If yes, when? Why were those doses missed? 
3. What concerns or questions do you have about continuing to take your 
tacrolimus “under the tongue”?