Tacrolimus in CD3+ T Lymphocytes (INTACT)

The Intracellular Pharmacokinetics of Tacrolimus in CD3+ T Lymphocytes

The goal of this study is to measure concentrations of the drug tacrolimus in both whole blood and within T lymphocytes. It will also learn on the correlation between the concentration in T lymphocytes and the effects of the drug. The main questions are:

(i) What is the ratio between the tacrolimus concentration within T lymphocytes and in whole blood?; (ii) What is the correlation between tacrolimus concentrations and the effects of the drug?

Participants will:

• Receive standard clinical care;
• Undergo two extra venipunctures for the collection of blood.

Study Overview

• Status: Completed
• Conditions: Immunosuppression
• Intervention / Treatment: Procedure: Venipunctures

Detailed Description

Rationale: The immunosuppressive drug tacrolimus is routinely monitored after kidney transplantation by measuring the whole blood, pre-dose concentration (C0). However, the C0 has a poor correlation with clinical events, most notably the risk of acute rejection. Since tacrolimus' site of action is within immune cells, the intracellular tacrolimus concentration in peripheral blood mononuclear cells (PBMCs) has recently been proposed to better represent the active concentration. However, several studies could not demonstrate an association between the intracellular tacrolimus concentration and acute rejection. One of the possible explanations for this surprising finding is the fact the PBMC fraction is composed of several cells including lymphocytes and monocytes. In this study, the tacrolimus concentration in CD3+ T lymphocytes will be investigated as this may be a more relevant cell population than PBMCs.

Objective: To prospectively measure the intracellular tacrolimus concentration in CD3+ T lymphocytes in kidney transplant recipients. The area under the concentration-vs-time curve (AUC) of the intracellular tacrolimus concentration will be determined and used for the development of a population pharmacokinetic model. The pharmacokinetics of intra-CD3+ tacrolimus will be compared with the whole-blood concentration and will be related to important clinical events.

Study design: Observational study with additional blood sampling. Study population: Twenty-five de novo kidney transplant recipients receiving once-daily tacrolimus- as maintenance immunosuppression.

Intervention: Two extra venipunctures for the collection of blood.

• Study Type: Observational
• Enrollment (Actual): 28

Contacts and Locations

Study Locations

• Netherlands
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus MC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Recipients of a kidney transplant at the Erasmus MC who receive routine tacrolimus-based immunosuppression as part of routine clinical care.

Description

Inclusion Criteria:

• Age ≥ 18 years.
• Receive a kidney transplant at Erasmus MC.
• Use once-daily tacrolimus as part of routine maintenance immunosuppression starting the day of surgery.
• Written informed consent.

Exclusion Criteria:

• Receive lymphocyte depleting agents (thymoglobulin, anti-thymocyte globulin, and alemtuzumab) as an induction therapy or anti-rejection treatment before the enrolment (lymphocyte depleting agents will lower the amount of CD3+ T lymphocytes to the level that they cannot be isolated for the measurement of intracellular tacrolimus concentration).

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
De novo kidney transplant recipients; Intervention: Two extra venipunctures for the collection of blood. Drug: Once-daily extended-release tacrolimus formulation with a standard, body-weight-based starting dose of 0.14 mg/kg/day	Procedure: Venipunctures; Extra venipunctures

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The intracellular tacrolimus concentration in CD3+ T lymphocytes	The tacrolimus concentration in T lymphocytes will be measured by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The concentration measured is reported in μg/L. The intracellular tacrolimus concentration will then be calculated and reported in pg/million cells (range 5-1,250 pg/million cells).	Follow-up to one month post-transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracellular cytokine production	=CD3+ T lymphocytes will be stimulated in vivo by CD3/CD28 magnetic beads overnight. Cytokines produced by CD3+ T lymphocytes, including IL-2 and IFN-γ, will be measured by the intracellular staining under flow cytometry.	Follow-up to one month post-transplantation

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Investigators: Principal Investigator: Brenda C.M. de Winter, PharmD, PhD, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2022
• Primary Completion (Actual): October 10, 2022
• Study Completion (Actual): November 10, 2022

Study Registration Dates

• First Submitted: March 26, 2024
• First Submitted That Met QC Criteria: March 26, 2024
• First Posted (Actual): April 2, 2024

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: March 26, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Tacrolimus; Kidney transplantation; Intracellular T lymphocyte concentration
• Other Study ID Numbers: MEC-2022-0037

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No