Clinical trial NCT06338306: Tacrolimus and Personalized Therapy to Prevent Acute Rejection Episodes
Official title: Therapeutic Drug Monitoring of Tacrolimus Personalized Therapy in Heart Transplantation: New Strategies
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Heart Transplant Failure
Keywords: Tacrolimus
Whole Blood
PBMCs
Endomyocardial biopsy
Acute rejection
Therapeutic Drug Monitoring (TDM)
Lead sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia
Sponsor class: OTHER
First posted: 2024-03-29
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Twenty-five de-novo heart transplant recipients will be enrolled, male and female, aging 18-70 years, receiving TAC in combination with steroids and antiproliferative drugs (MMF; EC-MPS) or m-TOR inhibitors (Everolimus; Sirolimus).

Brief summary: Heart transplant is the only effective treatment for people with advanced heart failure.

Post-transplant pharmacological therapies are of fundamental importance for the survival of individuals after surgery: although considerable progress has been made for combined immunosuppressive therapies, acute cellular and especially non-cellular rejection still represents a great challenge for doctors.

To verify the absence of the first signs of acute rejection, the analysis of numerous cardiac biopsies (EMB endomyocardial biopsies) is necessary during the first 12 months following the transplant.

Thanks to these scheduled checks, doctors are able to identify the first symptoms of possible chronic rejection and reduce its episodes.

Since the analysis of biopsies is also based on subjective interpretations, cases of erroneous conclusions are frequent.

The researchers of this study aim not only to analyze the biopsies according to the current best clinical practice, but also to evaluate how much anti-rejection drug is actually contained within them.

This is an analysis that is still little used for this type of transplant, which could provide very useful information to doctors.

The researchers will focus their attention on one drug in particular, tacrolimus, abbreviated to "TAC".

The amount of drug measured in biopsies will be compared with that measured in whole blood samples and in particular blood cells (peripheral blood mononuclear cells: PBMC).

The genetic characteristics of each person play an important role in the success of treatment with the drug. To best interpret the results, all participants will be asked to take a blood sample to identify some characteristics of their DNA that could influence the outcome of tacrolimus therapy.

Detailed description: Heart transplant is the only effective treatment for people with advanced heart failure. Major advances in allograft protection, such as improved combined immunosuppressive therapies, have led to progressive increases in post-transplant survival, but acute cellular and especially non-cellular rejection still represents a challenge for clinicians. Endomyocardial biopsy (EMB) is the current standard of care used to identify rejection after HTx, with at least 13 biopsies scheduled within the twelve months following transplantation.

The mortality rate, after this period, is approximately 3.5% per year and the causes of death range from primary graft failure and multiorgan failure, to neoplasms, renal failure and cardiac allograft vasculopathy. Although acute rejection can be well managed in most cases, episodes of cumulative rejection and chronic rejection are likely to contribute to long-term graft failure and graft vasculopathy. The current ISHLT (International Society for Heart and Lung Transplantation) classification system provides categories of severity of rejection, for both cellular and antibody-mediated rejection. It describes the degree of tissue damage and infiltration by inflammatory cells and states that the greater the infiltrate, the worse the rejection. The purpose of the evaluation is to guide doctors in treating rejection before symptoms appear. However, histological reading, like any diagnostic technique, is subject to false positives and false negatives.

The researchers propose to monitor TAC trough concentrations directly in EMBs, during the first year after transplantation (5 scheduled biopsies), from at least 25 de novo heart transplant recipients. The results will be analyzed and correlated with whole blood and with the minimum concentrations of PBMC (peripheral blood mononuclear cells) detected, for each patient, in the same 5 scheduled follow-up visits. Pharmacogenetic studies will focus on CYP3A4, CYP3A5 and ABCB1 gene variants. The ABCB1 gene encodes P-glycoprotein (Pg-p), an ATP-driven transmembrane transporter that acts as an efflux pump and transports TAC out of PBMCs and tissues. These researchers hypothesize that elevated cardiac expression of P-gp may reduce TAC uptake into cardiac (donor) tissue, may act as an important modulator of immunosuppressive effects, and thus have important therapeutic implications.

Main objectives

Tacrolimus is a critically dosed drug and therapeutic drug monitoring is mandatory to avoid under- and overexposure. However, rejection and drug-related toxicity occur despite pre-dose whole blood (blood \[TAC\]) tacrolimus concentrations being on target. Monitoring tacrolimus concentrations at the target site (within peripheral blood mononuclear cells (\[TAC\] cells)) and directly in endomyocardial biopsies (\[TAC\] EMB)) may better correlate with treatment efficacy.

The objectives of this study are:

1. study TAC trough concentrations in whole blood (blood \[TAC\]), PBMC (cells \[TAC\]), and EMB (\[TAC\]EMB) simultaneously, across 5 scheduled follow-up visits of 25 HTx recipients
2. identify genetic characteristics that influence the metabolism and distribution of tacrolimus in whole blood, cells and EMBs,
3. study the relationships between the three concentration profiles (\[TAC\]blood), \[TAC\]cells, \[TAC\]EMB) and clinical outcomes, during the first year after heart transplantation.

Eligibility criteria: Inclusion Criteria:

de novo heart transplant recipient

Exclusion Criteria:

* Age \< 18 years
* Intolerance to TAC or to some excipient
* Intolerance to glucose
* diabetes mellitus

Primary outcomes:
measure: Tacrolimus quantification in an unconventional matrix
timeFrame: 0.5, 1, 3, 6 and 12 months after heart transplantation
measure: Tacrolimus quantification in PBMCs
timeFrame: 0.5, 1, 3, 6 and 12 months after heart transplantation
measure: Tacrolimus quantification in whole blood
timeFrame: 0.5, 1, 3, 6 and 12 months after heart transplantation
Secondary outcomes:
measure: Genetic profile in heart transplant recipients
timeFrame: The pharmacogenetic investigation (PGx) will be carried out at enrollment
Other outcomes:
Locations:
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
Study officials:
References:
citation: Molinaro M, Pellegrini C, Cattadori B, De Gregori S. Development and validation of a combined enzymatic-digestion/mass spectrometry assay for Tacrolimus quantitation in cardiac biopsies. J Chromatogr B Analyt Technol Biomed Life Sci. 2020 Sep 1;1152:122215. doi: 10.1016/j.jchromb.2020.122215. Epub 2020 Jun 21.