Abstract
Background
LCPT (Envarsus XR®) is a common once-daily, extended-release oral tacrolimus formulation used in kidney transplantation. However, there are minimal evidence-based recommendations regarding optimal dosing and treatment in the de novo and conversion settings.
Material/Methods
Using Delphi methodology, 12 kidney transplantation experts with LCPT experience reviewed available data to determine potential consensus topics. Key statements regarding LCPT use were generated and disseminated to the panel in an online Delphi survey. Statements were either accepted, revised, or rejected based on the level of consensus, perceived strength of evidence, and alignment with clinical practice. Consensus was defined a priori as ≥75% agreement.
Results
Twenty-three statements were generated: 14 focused on de novo LCPT use and 9 on general administration or LCPT conversion use. After 2 rounds, consensus was achieved for 11/14 of the former and 7/9 of the latter statements. In a de novo setting, LCPT was recognized as a first-line option based on its safety and efficacy compared to immediate-release tacrolimus. In particular, African Americans and rapid metabolizer populations were identified as preferred for first-line LCPT therapy. In a conversion setting, full consensus was achieved for converting to LCPT to address neurological adverse effects related to immediate-release tacrolimus and for the time required (approximately 7 days) for steady-state LCPT trough levels to be reached.
Conclusions
When randomized clinical trials do not replicate current utilization patterns, the Delphi process can successfully generate consensus statements by expert clinicians to inform clinical decision-making for the use of LCPT in kidney transplant recipients.
Keywords: Delphi Technique, Kidney Transplantation, Tacrolimus
Background
Formulations of tacrolimus in combination with other immunosuppressants are used in the overwhelming majority of kidney transplant recipients for the prevention of organ rejection [1,2]. After the initial approval of FK506 (Prograf) for kidney transplantation in 1997, several tacrolimus formulations have been studied and approved for use. Most recently, once-daily preparations of tacrolimus have gained United States (US) Food and Drug Administration (FDA) indications for use, both in the de novo setting and for conversion from twice-daily preparations in clinically stable patients following kidney transplantation [3,4]. Potential advantages of once-daily preparations include lower pill burden, greater adherence, and the potential to modify adverse effect profiles associated with pharmacokinetic differences [5–9].
LCPT (Envarsus XR® tablets [Life-Cycle Pharma Tacrolimus], Veloxis Pharmaceuticals, Cary, North Carolina) is a once-daily formulation used to prevent rejection in both de novo kidney transplant patients and patients converted from immediate-release tacrolimus (IR-Tac) formulations [3]. Unlike IR-Tac formulations such as twice-daily Prograf® capsules (Astellas Pharma, Inc., Tokyo, Japan) and once-daily Astagraf XL® capsules (Astellas Pharma, Inc., Tokyo, Japan), once-daily LCPT has been shown to have a smoother, lower-peak pharmacokinetic profile [10–12]. In addition, LCPT maintains target trough levels and avoids the higher peak levels associated with these other tacrolimus formulations [13]. The efficacy of the LCPT extended-release delivery system [14] has been demonstrated in difficult-to-treat patient types, such as rapid metabolizers [15].
Clinical guidelines in kidney transplantation published by KDIGO (Kidney Disease: Improving Global Outcomes) in 2009 recommend using tacrolimus as the first-line calcineurin inhibitor combined with other immunosuppressants for the initial treatment and long-term maintenance of kidney transplantation patients [16]. These guidelines also include recommendations for immunosuppressive therapy to help reduce the cost of these drugs, monitor immunosuppression, and prevent, detect, and treat non-adherence [16]. However, these KDIGO guidelines have not been updated since newer tacrolimus formulations have become available. While phase III data defined the safety and efficacy of LCPT, these studies were performed during an era in which induction therapy evolved away from nondepleting to depleting antibody therapy [2].
Transplant clinicians lack randomized clinical trial data guiding the real-world use of LCPT, and uncertainty remains on how best to use LCPT in kidney transplantation. For instance, the recommended starting dose for LCPT of 0.14 mg/kg is higher than that of IR-Tac since it was decided prior to the FDA decision to lower the recommended starting dose of IR-Tac, and acceptance of this dose among prescribers is unknown [3,17]. Furthermore, the reason(s) for conversion to LCPT and the ideal candidates for LCPT therapy have not been established.
Given these gaps in published data, and the lack of additional randomized controlled trials to address these unresolved issues, a need exists to reach a clinical consensus on best practices for the use of once-daily LCPT in kidney transplantation in a real-world setting. The objective of this study was to address this need by developing a consensus document on the use of LCPT in kidney transplantation using the Delphi process. The Delphi process is an established structured technique to aid consensual group decision-making by experts based on feedback, in the absence of data from robust clinical studies [18,19]. This consensus document aims to inform decision-making for clinicians considering the use of LCPT, educate clinicians on best practices around the use of LCPT in kidney transplantation, and increase awareness of LCPT.
Material and Methods
A panel of clinicians was assembled to participate in developing the LCPT consensus document using the Delphi process [18,19]. When good quality clinical study data are scarce or non-existent, the Delphi process can provide a structured communication technique for obtaining agreement from a group of expert panelists using anonymous feedback in research areas where data are incomplete [19]. Delphi methodology has been widely and successfully used in clinical studies [9,20,21], including contemporary studies of kidney transplantation [22–26]. The Delphi methodology used in our study was similar to that used in other modern clinical studies [9,21].
Advantages of the Delphi process include generating consensus based on panel expertise, removing the pressure to conform by maintaining anonymity, reducing the impact of outspoken or senior experts, and providing experts with the time and space to consider summarized feedback from the whole panel. Panelists were selected by the panel co-chairs (AW, SB) based on their expertise and work in nephrology and kidney transplantation, representing a broad range of practice settings and geographical locations, with the aim of including medical specialists involved in the care and management of kidney transplant recipients.
Development of the Delphi Panel Questionnaire
In January 2022, as part of the unblinded preparation phase of the Delphi panel survey of LCPT use in kidney transplantation (Figure 1), panelists viewed pre-recorded data selected by the panel co-chairs that summarized the available clinical evidence. The recordings covered relevant studies evaluating the pharmacokinetics [13,27–30], pharmacogenetics [30], dosing [31], and efficacy and safety of LCPT [27–29,32]. Following review, topics for which consensus was needed were identified and agreed upon by the panel co-chairs (AW and SB) and study team (Evidera). These topics included: important unresolved questions of the scientific community related to the use of LCPT in kidney transplantation, LCPT in the de novo setting, LCPT in the conversion setting, rating the quality of evidence for LCPT, and special populations (eg, rapid metabolizers, the elderly, African Americans), adverse effects (eg, neurologic, impaired glucose tolerance), and adherence concerns. A pre-meeting survey for all panel members was collected based on these topics, forming the basis of future discussion. A workshop was convened where findings from the survey were shared, and panelists explained the rationale behind their survey responses and debated topics raised in the discussion. Workshops provide a valuable way to raise issues for consideration and are a common part of the Delphi process in many studies [9,21]. Our workshop resulted in the development of the Delphi panel questionnaire.
Figure 1.
Delphi study flow chart. Software used for the creation of the figure: PowerPoint (version 2310, Microsoft). LCPT – once-daily extended-release oral tacrolimus.
Delphi Panel Survey
The execution phase of the Delphi panel survey of LCPT use in kidney transplantation consisted of 3 blinded rounds, 2 survey rounds, and 1 interpretation/consolidation and consensus round (Figure 1). Round 1 of the Delphi panel survey consisted of 12 open-ended online survey questions and was completed by panelists between April 12–23, 2022. Round 2 consisted of 6 open-ended and 18 close-ended online survey questions and was completed between July 28–August 15, 2022, following an additional email round for consensus on 1 statement. Consensus for a statement was achieved when ≥75% (at least 9 of 12 panelists) responded “agree strongly” or “agree with reservation.” Panelists with reservations could explain what these were in detail using an open dialogue box in the survey, and these comments were considered in the revision of statements. Other options available included “disagree strongly,” “disagree,” and “undecided.”
Results
Development of the Delphi Panel Questionnaire
The panel of 12 experienced clinicians, with an average of 19.4±6.6 years in practice, consisted of 9 nephrologists, 2 pharmacists, and 1 surgeon. Eleven of the 12 panelists were from centers that transplanted over 100 transplants per year, and the collective transplant volume of the centers represented by the panelists was ~10% of the number of transplants performed annually in the US. Panelists were in clinical leadership positions at their institutions and spent over half their time (53%) on direct patient or transplant-related care and approximately a quarter (23%) on research. The primary practice setting was an academic teaching hospital for 10 out of 12 panelists and a non-academic teaching hospital for the remaining 2. Individual assessments of the quality of evidence for LCPT are shown in Table 1 for special populations and in Table 2 for adverse effects. Ten panelists felt there were more unresolved questions about LCPT to be addressed in a de novo setting than in a conversion setting.
Table 1.
Quality of published evidence: patient populations for LCPT.
| Panelist | |||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 |
| Rapid metabolizers | |||||
| Moderate | High | Moderate | Moderate | High | Moderate |
| Elderly population | |||||
| Low | Moderate | Low | Low | High | Low |
| African American population | |||||
| Moderate | Moderate | High | Moderate | High | Moderate |
| Other | |||||
| Very low | Moderate | Moderate | Low | Moderate | Very low |
| N/A | Others | Asian Americans | Hispanics | Other ethnic groups, like Hispanics and Asians | Patients with gastric bypass or sleeve/other GI manipulation |
| Panelist | |||||
| 7 | 8 | 9 | 10 | 11 | 12 |
| Rapid metabolizers | |||||
| High | High | High | Moderate | Moderate | Moderate |
| Elderly population | |||||
| Moderate | Moderate | Low | Low | Low | Low |
| African American population | |||||
| Moderate | Moderate | Moderate | Moderate | Moderate | Moderate |
| Other | |||||
| Low | Low | Low | Moderate | Very low | Very low |
|
|
Patients who have compliance concerns | Neurocognitive side effects | N/A |
|
DGF – delayed graft function; GI – gastrointestinal; N/A – not applicable.
Table 2.
Quality of published evidence: adverse effects with LCPT.
| Panelist | |||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 |
| Neurologic side effects | |||||
| Low | Moderate | High | Moderate | High | Low |
| Impaired glucose tolerance | |||||
| Very low | Low | Low | Very low | Low | Low |
| Adherence concerns | |||||
| Low | Moderate | Low | Low | Moderate | Moderate |
| Other | |||||
| Very low | Low | Low | Low | Low | Low |
| N/A | The rest | N/A |
|
|
N/A |
| Panelist | |||||
| 7 | 8 | 9 | 10 | 11 | 12 |
| Neurologic side effects | |||||
| High | Moderate | High | Moderate | Moderate | Low |
| Impaired glucose tolerance | |||||
| Moderate | Low | Moderate | Low | Low | Moderate |
| Adherence concerns | |||||
| Moderate | Low | Moderate | Low | Low | Low |
| Other | |||||
| Moderate | Low | Low | Low | Very low | Low |
|
N/A | N/A |
|
N/A |
|
DGF – delayed graft function; N/A – not applicable; NODAT – new-onset diabetes after transplantation; QOL – quality of life.
Delphi Panel Survey
Based on the post-workshop memorandum and identified topics of interest, a total of 23 statements for consensus were generated for round 1 and categorized by setting – de novo versus conversion – and by topic: (1) clinical use of LCPT, (2) general dosing guidelines, and (3) challenges to using LCPT. Fifteen of the original statements were statements addressing the de novo setting, 7 were statements addressing the conversion setting, and 1 original statement addressed both settings.
In round 1, consensus was achieved for 9/15 statements on the clinical use of LCPT, and 2/4 statements on general dosing guidelines 2/4 statements on challenges to using LCPT (Figure 2, Tables 3, 4). No further revision was carried out on 5 statements from round 1: 3 statements were dropped due to a sizeable lack of consensus, weak evidence, and/or poor alignment of the statement with clinical practice, and 2 statements were merged to create a new statement in round 2. In round 2, a total of 6 modified statements from round 1 were administered to panelists. Consensus was achieved for all 6 statements: 3/3 statements on the clinical use of LCPT, 1/1 for general dosing guidelines, and 2/2 statements on challenges to using LCPT (Figure 2, Tables 3, 4).
Figure 2.
LCPT consensus statement flow chart. Software used for the creation of the figure: PowerPoint (version 2310, Microsoft). LCPT – once-daily extended-release oral tacrolimus.
Table 3.
Delphi statement progression, LCPT (Envarsus XR®) use in a de novo setting.
| Original statement for consensus* | Status Round 1 | Action Round 2 | Final statusa | Final consensus | Final statement* |
|---|---|---|---|---|---|
| Clinical use of LCPT | |||||
| 1. In the de novo setting, Envarsus XR® can be used as first-line therapy considering its efficacy and safety are equivalent to BID tacrolimus. Sub questions: for round 1 only to seek agreement on: A. similar efficacy (biopsy-proven acute rejection (BPAR) and graft survival at 12 months B. similar safety profile | Consensus | Consensus after R1 | 92% | In the de novo setting, Envarsus XR® can be used as first-line therapy considering its efficacy and safety are equivalent to BID tacrolimus. A. Envarsus XR® has a similar efficacy profile as tacrolimus IR B. Envarsus XR® has a similar safety profile as tacrolimus IR | |
| Compared to twice-daily tacrolimus… 2. When considering safety and efficacy, Envarsus XR® is not recommended as first-line therapy in patients with significant pre-existing GI motility issues in the de novo settingb | No consensus | No further revisions due to very low consensus, low to moderate perceived strength of evidence and alignment with clinical practice | Dropped after Round 1 | 41% | N/A |
| Compared to twice-daily tacrolimus… 3. When considering safety and efficacy, Envarsus XR® is preferred as first-line therapy for African American patient population in the de novo setting | Consensus | Consensus after R1 | 83% | Compared to twice-daily tacrolimus…. When considering safety and efficacy, Envarsus XR® is preferred as first-line therapy for African American patient population in the de novo setting | |
| Compared to twice-daily tacrolimus… 4. When considering safety and efficacy, Envarsus XR® is preferred as first-line therapy for elderly patient population in the de novo setting. | No consensus | No further revisions due to low consensus, a lack of supporting evidence and low-to-moderate alignment with clinical practice | Dropped after Round 1 | 58% | N/A |
| Compared to twice-daily tacrolimus… 5. When considering safety and efficacy, Envarsus XR® is preferred as first-line therapy in known rapid metabolizers in the de novo setting | Consensus | Consensus after R1 | 91% | Compared to twice-daily tacrolimus…. When considering safety and efficacy, Envarsus XR® is preferred as first-line therapy as first-line therapy in known rapid metabolizers in the de novo setting | |
| Compared to twice-daily tacrolimus… 6. When considering safety and efficacy, Envarsus XR® is preferred as first-line therapy in patients with high immunologic risk in the de novo setting | No consensus | No further revisions due to to very low consensus, low perceived strength of evidence and moderate alignment with clinical practice | Dropped after Round 1 | 25% | N/A |
| 7. In the de novo setting, the first assessment of trough levels of Envarsus XR® should be after the third dose | No consensus | Statement revised for consensus in Round 2 | Consensus after R2 | 92% | In the de novo setting, the first assessment of trough levels of Envarsus XR® can be after the third dose although steady state is not expected until after 7 days on a stable dose |
| 8. In the de novo setting, the Envarsus XR® dosing should begin with 0.14 mg/kg/day for all kidney transplant recipients | No consensus | Statement revised for consensus in Round 2 | Consensus after R2b (email round) | 92% | In the de novo setting, the Envarsus XR® dosing should begin with 0.14 mg/kg/day and should be calculated for ideal body weight in the setting of obesity, except in the following scenarios: A. The initial dosing of Envarsus XR® may be reduced in the setting of depleting antibody therapy when using induction therapy B. The dose may be increased in known rapid metabolizers. C. The dose may be adjusted in the presence of known drug interactions that influence tacrolimus metabolismc |
| 8a. In the de novo setting, ideal body weight should be used as the preferred initial dosing weight for Envarsus XR® in obese recipients | Consensus | Consensus after R1 | 100% | In the de novo setting, ideal body weight should be used as the preferred initial dosing weight for Envarsus XR® in obese recipients | |
| 9. In the de novo setting, Envarsus XR® should be initiated on the morning of POD1 for all kidney transplant recipients, regardless of initial kidney function | Consensus | Consensus after R1 | 83% | In the de novo setting, Envarsus XR® should be initiated on the morning of POD1 for all kidney transplant recipients, regardless of initial kidney function | |
| 10. In the de novo setting, initial dosing of Envarsus XR® can be reduced in the setting of depleting antibody therapy when using induction therapy | Consensus | Consensus after R1 | 83% | In the de novo setting, initial dosing of Envarsus XR® can be reduced in the setting of depleting antibody therapy when using induction therapy | |
| 11. In the de novo setting, initial dosing of Envarsus XR® can be reduced in patients for whom the risk of supratherapeutic levels outweighs the benefit of rapid achievement of therapeutic levels (e.g., delayed graft function, seizure patients, low immunologic risk) | No consensus | Statement revised for consensus in Round 2 | Consensus after R2 | 100% | In the de novo setting, initial dosing of Envarsus XR® can be adjusted in patients for whom the risk of supratherapeutic levels outweighs the benefit of rapid achievement of therapeutic levels |
| 12. During the first week post-transplant the dose of Envarsus XR® should only be adjusted in circumstances of a supratherapeutic level or circumstances of a significantly subtherapeutic trough level suggestive of rapid metabolism (e.g., tacrolimus trough <3 ng/ml after postoperative day 3) | Consensus | Consensus after R1 | 75% | During the first week post-transplant the dose of Envarsus XR® should only be adjusted in circumstances of a supratherapeutic level or circumstances of a significantly subtherapeutic trough level suggestive of rapid metabolism (e.g., tacrolimus trough <3 ng/ml after postoperative day 3) | |
| 13. Conversion to Envarsus XR® is recommended to address neurological side-effects related to BID Tacrolimus | Consensus | Consensus after R1 | 100% | Conversion to Envarsus XR® is recommended to address neurological side-effects related to BID Tacrolimus | |
| 14. Steady state is achieved after Envarsus XR® dose 7 and therefore, on a stable dose, dose adjustments can be made per clinical practice protocols following the seventh dose | Consensus | Consensus after R1 | 75% | Steady state is achieved after Envarsus XR® dose 7 and therefore, on a stable dose, dose adjustments can be made per clinical practice protocols following the seventh dose | |
| Challenges to using LCPT | |||||
| 15. Further evidence of clinical long-term outcomes (graft survival, renal function) is needed to support the use of Envarsus XR® to influence changes to current clinical practice, in both the de novo setting and conversion setting | No consensus | Statement revised for consensus in Round 2 | Consensus after R2 | 92% | Further evidence of clinical long-term outcomes (graft survival, renal function) would help support the use of Envarsus XR® in current clinical practice, in both the de novo setting and conversion setting |
BID – twice a day; GI – gastrointestinal; POD1 – post-operative day 1.
Consensus was set at ≥75% (at least 9 of the 12 panelists). Final consensus was agreed by all 12 panelists;
No further revisions due to very low consensus, low-to-moderate perceived strength of evidence, and lack of alignment with clinical practice;
Consensus was achieved after 1 round of e-mails after round 2 for this statement only.
Underlined text in an original statement for consensus indicates wording that has been altered or deleted. Underlined text in a final statement indicates wording that has been altered or added.
Table 4.
Delphi statement progression, LCPT (Envarsus XR®) use in a conversion setting.
| Original statement for consensus* | Status Round 1 | Action Round 2 | Final statusa | Final consensus | Final statement* |
|---|---|---|---|---|---|
| General dosing guidelines for LCPT | |||||
| 16. Patients should consistently take Envarsus XR® on an empty stomach, rather than consistently with or without food | Consensus | Consensus after R1 | 92% | Patients should consistently take Envarsus XR® on an empty stomach, rather than consistently with or without food | |
| 17. When available, pharmacogenomic screening is recommended for initial dosing considerations for Envarsus XR® for all patients | No consensus | Merged with Statement 18 | No consensus in R1, merged after R1 to create Statement 20 | ||
| 18. When available, pharmacogenomic screening is recommended for initial dosing considerations for Envarsus XR® only for specific patient populations | No consensus | Merged with Statement 17 | No consensus in R1, merged after R1 to create Statement 20 | ||
| 19. Trough level assessment of Envarsus XR® should take into account the time to achieve steady state (approximately 7 days) | Consensus | Consensus after R1 | 100% | Trough level assessment of Envarsus XR® should take into account the time to achieve steady state (approximately 7 days) | |
| 20. No original statement in Round 1. New statement developed in Round 2 | N/A | Statements 17 and 18 were combined in Round 2 | Consensus after R2 | 83% | When available, pharmacogenomic screening is recommended for initial dosing considerations for Envarsus XR ® |
| Challenges to using LCPT | |||||
| 21. Additional cost and formulary considerations pose barriers to the use of Envarsus XR® as first line therapy in the de novo setting | Consensus | Consensus after R1 | 75% | Additional cost and formulary considerations pose barriers to the use of Envarsus XR® as first line therapy in the de novo setting | |
| 22. Additional costs and staff time required pose barriers to conversion to Envarsus XR® | Consensus | Consensus after R1 | 91% | Additional costs and staff time required pose barriers to conversion to Envarsus XR® | |
| 23. There are no specific recommendations for utilization of Envarsus XR® related to intrapatient variability, given similar intrapatient variability with all tacrolimus preparations | No consensus | Statement revised for consensus in Round 2 | Consensus after R2 | 83% | Intrapatient variability has been shown with tacrolimus preparations. There are no specific recommendations for utilization of Envarsus XR® related to intrapatient variability |
| 3. Further evidence of clinical long-term outcomes (graft survival, renal function) is needed to support the use of Envarsus XR® to influence changes to current clinical practice, in both the de novo setting and conversion setting | No consensus | Statement revised for consensus in Round 2 | Consensus after R2 | 92% | Further evidence of clinical long-term outcomes (graft survival, renal function) would help support the use of Envarsus XR® in current clinical practice, in both the de novo setting and conversion setting |
Consensus was set at ≥75% (at least 9 of the 12 panelists). Final consensus was agreed by all 12 panelists.
Underlined text in an original statement for consensus indicates wording that has been altered or deleted. Underlined text in a final statement indicates wording that has been altered or added.
The final recommendations on the use of LCPT (Envarsus XR®) in kidney transplantation are summarized in Table 5. Consensus was achieved on the use of LCPT in kidney transplantation for 12 de novo setting statements, 6 conversion setting statements, and 1 statement common to both settings.
Table 5.
Final recommendations on the use of LCPT (Envarsus XR®) in kidney transplantation.
| Final recommendation/statement | Consensus |
|---|---|
| De novo setting | |
| In the de novo setting, Envarsus XR® can be used as first-line therapy considering its efficacy and safety are equivalent to BID tacrolimus Subquestions for round 1 only to seek agreement on: A. Envarsus XR® has a similar efficacy profile as tacrolimus IR B. Envarsus XR® has a similar safety profile as tacrolimus IR |
92% |
| Compared to twice-daily tacrolimus… When considering safety and efficacy, Envarsus XR® is preferred as first-line therapy for African American patient population in the de novo setting | 83% |
| Compared to twice-daily tacrolimus… When considering safety and efficacy, Envarsus XR® is preferred as first-line therapy in known rapid metabolizers in the de novo setting | 83% |
| In the de novo setting, the first assessment of trough levels of Envarsus XR® can be after the third dose although steady state is not expected until after 7 days on a stable dose | 92% |
| In the de novo setting, the Envarsus XR® dosing should begin with 0.14 mg/kg/day and should be calculated for ideal body weight in the setting of obesity, except in the following scenarios: A. The initial dosing of Envarsus XR® may be reduced in the setting of depleting antibody therapy when using induction therapy B. The dose may be increased in known rapid metabolizers C. The dose may be adjusted in the presence of known drug interactions that influence tacrolimus metabolism | 92% |
| In the de novo setting, ideal body weight should be used as the preferred initial dosing weight for Envarsus XR® in obese recipients | 100% |
| In the de novo setting, Envarsus XR® should be initiated on the morning of POD1 for all kidney transplant recipients, regardless of initial kidney function | 83% |
| In the de novo setting, initial dosing of Envarsus XR® can be reduced in the setting of depleting antibody therapy when using induction therapy | 83% |
| In the de novo setting, initial dosing of Envarsus XR® can be adjusted in patients for whom the risk of supratherapeutic levels outweighs the benefit of rapid achievement of therapeutic levels | 100% |
| During the first week post-transplant the dose of Envarsus XR® should only be adjusted in circumstances of a supratherapeutic level or circumstances of a significantly subtherapeutic trough level suggestive of rapid metabolism (e.g., tacrolimus trough <3 ng/ml after postoperative day 3) | 75% |
| Conversion to Envarsus XR® is recommended to address neurological side-effects related to BID Tacrolimus | 100% |
| Steady state is achieved after Envarsus XR® dose 7 and therefore, on a stable dose, dose adjustments can be made per clinical practice protocols following the seventh dose | 75% |
| Further evidence of clinical long-term outcomes (graft survival, renal function) would help support the use of Envarsus XR® in current clinical practice, in both the de novo setting and conversion setting | 92% |
| Conversion setting | |
| Patients should consistently take Envarsus XR® on an empty stomach, rather than consistently with or without food | 92% |
| Trough level assessment of Envarsus XR® should take into account the time to achieve steady state (approximately 7 days) | 100% |
| When available, pharmacogenomic screening is recommended for initial dosing considerations for Envarsus XR® | 83% |
| Additional cost and formulary considerations pose barriers to the use of Envarsus XR® as first line therapy in the de novo setting | 75% |
| Additional costs and staff time required pose barriers to conversion to Envarsus XR® | 92% |
| Intrapatient variability has been shown with tacrolimus preparations. There are no specific recommendations for utilization of Envarsus XR® related to intrapatient variability | 83% |
| Further evidence of clinical long-term outcomes (graft survival, renal function) would help support the use of Envarsus XR® in current clinical practice, in both the de novo setting and conversion setting | 92% |
BID – twice a day; GI – gastrointestinal; IR – immediate release; POD1 – post-operative day 1.
Discussion
Delphi methodology is a proven research tool that can generate consensus recommendations in a more rigorous, unbiased manner than other methods when robust clinical trial data are not available. Using Delphi methodology, US clinical experts in kidney transplantation reached consensus on many aspects of the clinical use, use challenges, and general dosing associated with LCPT in kidney transplantation in both de novo and conversion settings. The findings of this Delphi consensus survey will help to fill knowledge gaps and provide guidance regarding utilization of once-daily LCPT in kidney transplantation in a real-world setting, particularly in the de novo setting.
Outstanding issues identified by panelists at the outset of the study included the initial dosing of LCPT as maintenance immunosuppressive medication in both de novo and conversion settings, methods for monitoring and achieving therapeutic levels using LCPT (especially in the context of interpatient variability), and agreement about logistical issues and suggestions for ways to address them (eg, treatment protocols, formulary listings, and impact on pharmacist time/resources). Our study has successfully addressed many of these areas with new consensus statements. Guidance regarding initial dosing of LCPT in the de novo setting with concurrent depleting antibody therapy (Table 3, Statements 8 and 10), and weight-based dosing considerations in the de novo setting (Table 3, Statement 8a), are important real-world issues that prior published data have not adequately addressed. Indications for conversion (eg, neurological adverse effects, patient subtypes) were critically considered based on existing data, and the Delphi panel was able to reach a consensus in providing recommendations for and against the use of LCPT (Table 4).
Expert opinion can supplement other forms of data derived from randomized multicenter trials, meta-analyses, or single-center published experiences and provide guidance for future areas needing study and attention. Several panelists noted the importance of demonstrating the value of LCPT compared with IR-Tac, beyond that which has been shown previously [10,28,29]. Several outcomes were highlighted for potential future study, including long-term survival, cost-effectiveness, glomerular filtration rate (GFR), and biomarkers, including donor-specific antibody (DSA). Other outcomes included associations of endpoints of area under the curve (AUC)/trough levels, patient-relevant outcomes including adherence, and quality-of-life assessments.
In addition to identifying the benefits of LCPT, panelists also acknowledged challenges with changing institution-specific treatment protocols or formulary listings for immunosuppressants. Often, institutional inertia is driven by a lack of experience using novel agents (here, LCPT). Providing guidance for initial dosing and monitoring in the de novo setting should assist in addressing clinical concerns regarding use, but additional logistical and institutional barriers exist. Some panelists mentioned the need for demonstrable benefits to make the change in mindset worthwhile. An existing challenge regarding the inclusion of LCPT in formularies is the absence of non-renal transplant indications.
Our study found that the quality of published evidence supporting the use of LCPT for special patient populations LCPT varied (Table 1). Care was taken evaluating the transplant literature, as separate concepts are sometimes intermingled; for instance, race, high immunologic risk, and rapid metabolism. For rapid metabolizers and African Americans, the quality of evidence was generally considered moderate-to-high, while for the elderly, the quality of evidence was considered low-to-moderate. The quality of evidence for other patient populations ranged from very low to moderate. Further research in these patient populations will be of value. It is uncertain whether dose requirements of LCPT differ for patients with gastric motility concerns (eg, diabetes and gastroparesis) due to a lack of evidence. In several cases, the lack of data to support the statements identified for consensus did not permit panelists to ratify certain statements despite their clinical importance (Figure 2).
Regarding the use of LCPT to address specific adverse effects, our study found a general lack of quality evidence (Table 2). The quality of evidence for neurological adverse effects was perceived to be the highest, with panelists’ ratings varying from low to high. The quality of evidence for adherence concerns was considered to be low-to-moderate, for impaired glucose tolerance it was very low-to-moderate, and for other adverse effects it was very low-to-low. Overall, the panelists found consensus in the recommendation for the use of LCPT in the setting of neurocognitive adverse effects for patients on an IR-Tac-based regimen.
Delphi methodology is a valuable tool for reaching consensus in areas of clinical management that lack sufficient data, but it is not without weaknesses. Disadvantages of Delphi methodology include variation in methods due to a lack of universally acknowledged guidelines, a lack of definition of what constitutes an “expert,” the small size of expert panels, and difficulties ensuring anonymity is guaranteed. To address these concerns, this study identified experts as clinicians with experience in treating kidney transplantation. It included panelists from different clinical backgrounds with attention to different geographic areas and practices, to provide additional expertise. Pros and cons exist for having clinical experience in LCPT. It might be perceived that panelists without personal clinical experience in LCPT are preferable as they would assess evidence on LCPT more objectively. However, it could be argued that panelists with experience using LCPT possess real-world insights that those without experience lack.
Although total anonymity was not maintained during the study as panelists met during the workshop, the workshop was not used to discuss consensus but to develop statements, and this type of workshop is a common feature in Delphi studies [9,21]. Following the development of consensus statements, the survey was conducted online, so panelists were unaware of any individual’s specific feedback. The wide variation in panelists’ assessments of priorities and of the strength of the literature should allay concerns of the scientific community about potential conflicts of interest and facilitate the acceptance of consensus statements generated by the study.
Conclusions
The Delphi process generated consensus statements by expert clinicians to inform clinical decision-making for the use of LCPT in de novo kidney transplant recipients and to guide the optimal use of LCPT in conversion kidney transplant recipients. These consensus statements provide a real-world guide to using LCPT in kidney transplantation, especially in a de novo setting, for which guidance is currently lacking. The consensus statements are particularly relevant to clinical practice, based on the clinical expertise of the panelists and the structured approach provided by Delphi methodology for developing and evaluating consensus statements.
Data Availability Statement
Data from this study are available from the corresponding author, Dr Alexander Wiseman, upon request.
Acknowledgements
The authors would like to thank Asha Hareendran, PhD, for her work in setting up the study and Tsion Fikre, MPH, for her support in executing the study. Medical writing assistance was provided by John Plant, BPharm. AH was an employee and TF and JP are current employees of Evidera, which was funded for this support by Veloxis.
Footnotes
Conflict of interest: RF, TA, FS, RA, CK, MC, NL, BC, AW, SB, and DT have received honoraria from Veloxis for participation in the pre-Delphi workshop. TA, FS, RA, CK, MC, AW, and SB have received speaker fees from Veloxis, and RF, RA, NL, AW, and SB have participated in an advisory board for Veloxis. VK has no conflicts of interest to declare. MH, DMB, and SM have no financial ties to Veloxis
Publisher’s note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher
Declaration of Figures’ Authenticity: All figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part.
Financial support: Funding for this survey was provided by Veloxis Pharmaceuticals, Inc.
References
- 1.Philosophe B, Leca N, West-Thielke PM, et al. Evaluation of flexible tacrolimus drug concentration monitoring approach in patients receiving extended-release once-daily tacrolimus tablets. J Clin Pharmacol. 2018;58(7):891–96. doi: 10.1002/jcph.1082. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Lentine KL, Smith JM, Miller JM, et al. OPTN/SRTR 2021 Annual Data Report: Kidney. Am J Transplant. 2023;23(2 Suppl 1):S21–S120. doi: 10.1016/j.ajt.2023.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.US Food and Drug Administration. Prescribing information – Envarsus XR® (Tacrolimus Extended-Release Tablets) 2015. [Accessed March 8, 2023]. https://www.envarsusxr.com/images/1188/envarsus-xr-pi-and-patient-medication-guide.pdf .
- 4.US Food and Drug Administration. Prescribing information – Astagraf XL® (Tacrolimus Extended-Release Capsules) 2015. [Accessed April 5, 2023]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204096s003s004lbl.pdf .
- 5.Tremblay S, Alloway RR. Clinical evaluation of modified release and immediate release tacrolimus formulations. AAPS J. 2017;19(5):1332–47. doi: 10.1208/s12248-017-0119-z. [DOI] [PubMed] [Google Scholar]
- 6.Sabbatini M, Garofalo G, Borrelli S, et al. Efficacy of a reduced pill burden on therapeutic adherence to calcineurin inhibitors in renal transplant recipients: An observational study. Patient Prefer Adherence. 2014;8:73–81. doi: 10.2147/PPA.S54922. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Valente G, Rinaldi L, Sgambato M, Piai G. Conversion from twice-daily to once-daily tacrolimus in stable liver transplant patients: Effectiveness in a real-world setting. Transplant Proc. 2013;45(3):1273–75. doi: 10.1016/j.transproceed.2013.02.021. [DOI] [PubMed] [Google Scholar]
- 8.Kuypers DR, Peeters PC, Sennesael JJ, et al. Improved adherence to tacrolimus once-daily formulation in renal recipients: A randomized controlled trial using electronic monitoring. Transplantation. 2013;95(2):333–40. doi: 10.1097/TP.0b013e3182725532. [DOI] [PubMed] [Google Scholar]
- 9.Nelson J, Alvey N, Bowman L, et al. Consensus recommendations for use of maintenance immunosuppression in solid organ transplantation: Endorsed by the American College of Clinical Pharmacy, American Society of Transplantation, and the International Society for Heart and Lung Transplantation. Pharmacotherapy. 2022;42(8):599–633. doi: 10.1002/phar.2716. [DOI] [PubMed] [Google Scholar]
- 10.Bunnapradist S, Rostaing L, Alloway RR, et al. LCPT once-daily extended-release tacrolimus tablets versus twice-daily capsules: A pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups. Transpl Int. 2016;29(5):603–11. doi: 10.1111/tri.12770. [DOI] [PubMed] [Google Scholar]
- 11.Oberbauer R, Bestard O, Furian L, et al. Optimization of tacrolimus in kidney transplantation: New pharmacokinetic perspectives. Transplant Rev (Orlando) 2020;34(2):100531. doi: 10.1016/j.trre.2020.100531. [DOI] [PubMed] [Google Scholar]
- 12.Brunet M, van Gelder T, Asberg A, et al. Therapeutic drug monitoring of tacrolimus-personalized therapy: Second consensus report. Ther Drug Monit. 2019;41(3):261–307. doi: 10.1097/FTD.0000000000000640. [DOI] [PubMed] [Google Scholar]
- 13.Tremblay S, Nigro V, Weinberg J, et al. A steady-state head-to-head pharmacokinetic comparison of all FK-506 (Tacrolimus) formulations (ASTCOFF): An open-label, prospective, randomized, two-arm, three-period crossover study. Am J Transplant. 2017;17(2):432–42. doi: 10.1111/ajt.13935. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Grinyó JM, Petruzzelli S. Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations. Expert Rev Clin Immunol. 2014;10(12):1567–79. doi: 10.1586/1744666X.2014.983903. [DOI] [PubMed] [Google Scholar]
- 15.Tan T, Bunnapradist S. Comparing the pharmacokinetics of extended-release tacrolimus (LCP-TAC) to immediate-release formulations in kidney transplant patients. Expert Opin Drug Metab Toxicol. 2021;17(10):1175–86. doi: 10.1080/17425255.2021.1974399. [DOI] [PubMed] [Google Scholar]
- 16.Kidney Disease: Improving Global Outcomes Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(Suppl 3):S1–155. doi: 10.1111/j.1600-6143.2009.02834.x. [DOI] [PubMed] [Google Scholar]
- 17.US Food and Drug Administration. Prescribing information – Prograf® (Tacrolimus Capsules/Injection For Intravenous Use) 2012. [Accessed April 3, 2023]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050709s031lbl.pdf .
- 18.Dalkey NC. Delphi (P-3704) Santa Monica, CA: RAND Corporation; 1967. pp. 1–10. [Google Scholar]
- 19.Hsu C, Sandford BA. The Delphi Technique: Making sense of consensus. Practical Assessment, Research, and Evaluation. 2007. [Accessed March 22, 2023]. https://scholarworks.umass.edu/pare/vol12/iss1/10 .
- 20.Antonini A, Stoessl AJ, Kleinman LS, et al. Developing consensus among movement disorder specialists on clinical indicators for identification and management of advanced Parkinson’s disease: A multi-country Delphi-panel approach. Curr Med Res Opin. 2018;34(12):2063–73. doi: 10.1080/03007995.2018.1502165. [DOI] [PubMed] [Google Scholar]
- 21.Johnson DA, Katz PO, Armstrong D, et al. The safety of appropriate use of over-the-counter proton pump inhibitors: an evidence-based review and Delphi consensus. Drugs. 2017;77(5):547–61. doi: 10.1007/s40265-017-0712-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Afrouzian M, Kozakowski N, Liapis H, et al. Delphi: A democratic and cost-effective method of consensus generation in transplantation. Transpl Int. 2023;36:11589. doi: 10.3389/ti.2023.11589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Habbous S, Barnieh L, Litchfield K, et al. A RAND-modified Delphi on key indicators to measure the efficiency of living kidney donor candidate evaluations. Clin J Am Soc Nephrol. 2020;15(10):1464–73. doi: 10.2215/CJN.03780320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Sautenet B, Tong A, Manera KE, et al. Developing consensus-based priority outcome domains for trials in kidney transplantation: A multinational Delphi survey with patients, caregivers, and health professionals. Transplantation. 2017;101(8):1875–86. doi: 10.1097/TP.0000000000001776. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Shrestha P, Van Pilsum Rasmussen SE, King EA, et al. Defining the ethical considerations surrounding kidney transplantation for frail and cognitively impaired patients: A Delphi study of geriatric transplant experts. BMC Geriatr. 2022;22(1):566. doi: 10.1186/s12877-022-03209-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Tonkin-Crine S, Pruthi R, Taylor DM, et al. Assessing consensus between UK renal clinicians on listing for kidney transplantation: A modified Delphi study. Transplant Direct. 2018;4(5):e343. doi: 10.1097/TXD.0000000000000782. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Rostaing L, Bunnapradist S, Grinyó JM, et al. Novel once-daily extended-release tacrolimus versus twice-daily tacrolimus in de novo kidney transplant recipients: Two-year results of phase 3, double-blind, randomized trial. Am J Kidney Dis. 2016;67(4):648–59. doi: 10.1053/j.ajkd.2015.10.024. [DOI] [PubMed] [Google Scholar]
- 28.Budde K, Bunnapradist S, Grinyo JM, et al. Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: One-year results of Phase III, double-blind, randomized trial. Am J Transplant. 2014;14(12):2796–806. doi: 10.1111/ajt.12955. [DOI] [PubMed] [Google Scholar]
- 29.Bunnapradist S, Ciechanowski K, West-Thielke P, et al. Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): The phase III randomized MELT trial. Am J Transplant. 2013;13(3):760–69. doi: 10.1111/ajt.12035. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Trofe-Clark J, Brennan DC, West-Thielke P, et al. Results of ASERTAA, a randomized prospective crossover pharmacogenetic study of immediate-release versus extended-release tacrolimus in African American kidney transplant recipients. Am J Kidney Dis. 2018;71(3):315–26. doi: 10.1053/j.ajkd.2017.07.018. [DOI] [PubMed] [Google Scholar]
- 31.Cibrik D, West-Thielke P, Patel SJ, et al. LCP-tacrolimus (LCPT; Envarsus XR) dosing considerations in de novo kidney transplant recipients. Am J Transplant. 2019;19(Suppl 3):5–1167. Abstract 527. [Google Scholar]
- 32.Langone A, Steinberg SM, Gedaly R, et al. Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): An open-label, multicenter, prospective phase 3b study. Clin Transplant. 2015;29(9):796–805. doi: 10.1111/ctr.12581. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data from this study are available from the corresponding author, Dr Alexander Wiseman, upon request.