Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplant (HCT)

Study Overview
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Brief Summary
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The purpose of this research study is to evaluate tacrolimus plasma concentrations in patients who will undergo an allogeneic hematopoietic stem cell transplant (HCT). The study aims to identify associations between plasma concentrations, baseline demographic characteristics, clinical lab parameters, and genetic factors. These associations will help clinicians determine the best starting dose for tacrolimus in order to minimize risks of aGVHD and tacrolimus-induced toxicities.

Detailed Description
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This study aims to evaluate tacrolimus concentration-time data to characterize tacrolimus inter-individual pharmacokinetic (PK) variability in adult patients who will receive HCT, and to associate concentration-time data, exposure and clearance data with important clinical endpoints such as acute graft-versus-host disease (aGVHD) and tacrolimus-induced toxicities. This study proposes to enroll 50 patients at University of North Carolina Medical Center (UNCMC) who will undergo allogeneic HCT, who will receive tacrolimus starting the third day prior to allogeneic HCT (Day -3) for aGVHD prophylaxis. This will be an observational study, and its goal will be to ideally collect baseline clinical and demographic data, concentration-time data for tacrolimus on Day -3 (3 days before the transplant), Day -2 (2 days before the transplant), Day -1 (one day before the transplant), and Day 0 (the day of the allogeneic HCT) for a full pharmacokinetic profile. A medical chart review will be conducted to extract data on tacrolimus-induced toxicities (i.e., acute kidney injury [AKI], hypertension, metabolic panel changes, etc.) and aGVHD incidence rate up to Day +100 (100 days post-allogeneic HCT). Blood will also be collected for genotyping and will also be collected after the transplant to obtain information for surrogate PD biomarkers of tacrolimus efficacy, such as interleukin 2 (IL2) production and quantifiable nuclear localization of the dephosphorylated nuclear-activated T cells (NFAT). These data will aid in the development of a population-based PK/pharmacodynamic (PD) model that will serve as the foundation for a proposed precision dosing approach to optimize tacrolimus dosing. One of the secondary endpoints will be time to aGVHD, which will be defined as the duration from D0 until the first occurrence of aGVHD, censored at 100 days post-allogeneic HCT (Day +100). In the case of haplo-transplant patients, they will receive tacrolimus starting on Day +5 (as opposed to on Day -3 in non-haplo-transplant recipients). Per standard of care, haplo-transplant patients are initiated on Day +5 (5 days after the transplant). Therefore, in these patients, serial blood draws will be collected on a similar timeline as the non-haplo-transplant patients, but in this case Day +5, Day +6 (6 days after the transplant), Day +7 (7 days after the transplant), and Day +8 (8 days after the transplant; Day +8 is when they reach steady-state). For the PD biomarker studies in haplo-transplant patients, blood draws will occur on Day +9 (9 days after the transplant), Day +16 (16 days after the transplant), and Day +23 (23 days after the transplant) (Figure 2). All other procedures will remain the same.

Official Title
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Development of a Population Pharmacokinetic Model to Optimize Tacrolimus Dosing in Adult Recipients of Allogeneic Hematopoietic Stem Cell Transplant.

Conditions
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Acute GVHD

Intervention / Treatment
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* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age Patients who will undergo their first HCT Patients who will start tacrolimus for aGVHD prophylaxis Patients who have provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information Exclusion Criteria: Patients who have cognitive impairments that could affect informed decision-making Patients who are incarcerated Patients started on a strong CYP3A4 inhibitor (i.e. posaconazole)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Adult patients of allogeneic hematopoietic HCT<br>Patients who receive their first allogeneic HCT transplant and who receive tacrolimus for aGVHD prophylaxis per standard of care. | Drug: Tacrolimus<br>* Patients will be enrolled into this group if they receive tacrolimus per standard of care. This is an observational study and no interventions will be made.<br>* Other names: Prograf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tacrolimus clearance | Patient's clearance calculated after the first day on tacrolimus and patient's clearance calculated after 5-6 doses of tacrolimus after they reach steady-state | Day +1 of tacrolimus administration to Day +4 of tacrolimus administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of aGVHD | The duration from the day of transplant to the first occurrence of aGVHD, censored at 100 days post-HCT. | Day +21 to Day +100 from HCT | 
| Incidence of tacrolimus-induced toxicities | The duration from the day of transplant to the first occurrence of tacrolimus-induced toxicities (AKI, hypertension, and metabolic abnormalities) | Day -3 to Day +100 from HCT | 
| Time to aGVHD | The duration from the day of transplant to the first occurrence of aGVHD, censored at 100 days post-HCT. | Day +21 to Day +100 from HCT | 
| Time to tacrolimus-induced toxicities (AKI, hypertension, metabolic panel abnormalities) | The duration from the day of transplant to the first occurrence of AKI, hypertension, and metabolic panel abnormalities, censored at 100 days post-HCT. | Day -3 to Day +100 from HCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tacrolimus, aGVHD, pharmacokinetics, pharmacodynamics, pharmacogenomics, CYP3A5 genetic polymorphisms