Efficacy of Achieving Early Target Trough Levels of Tacrolimus Using CYP3A5 Guided Dosing Versus Weight-based Dosing in a Multi-ethnic Population of Kidney Transplant Recipients in Singapore

NCT04825262 | Completed DMC

• 1 other identifier: 2019/2599
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators hypothesise that the adaptation of CYP3A5 genotype-based Tacrolimus (FK) dosing will lead to earlier FK target achievement and consequently, better clinical outcome after kidney transplantation (RTx). This study aims to shed light on the possible impact of CYP3A genotype-based FK dosing on FK target achievement and clinical outcome after RTx in a multi-ethnic population where current evidence is lacking. This data would be helpful to the physicians so that by knowing the genotype of the patient before undergoing transplantation, practitioners would be able to decide on the starting dose of FK so as to avoid low trough levels and risk of acute rejection or high trough levels and risk of nephrotoxicity.

Conditions

Kidney Transplant Rejection; Kidney Transplant; Complications

Keywords

kidney transplant; tacrolimus; CYP3A5; Pharmacogenomics

Outcome Measures

Primary Outcomes (2)

• Proportion of patients within the desired FK trough level at first steady state

  E.g. Proportion of patients within target FK levels on the morning of day 3 after five unaltered FK doses

  3 days

• Proportion of patients within the desired FK trough level at 7 days

  E.g. Proportion of patients within target FK levels on the morning of day 7 post initiation of FK

  7 days

Secondary Outcomes (10)

• Average FK level during the first 1 weeks after transplantation

  1 week

• Average daily dose of FK the first 90 days post transplantation [days 3, 7, 14±3, 30±3, 60±3, 90±3 days post transplantation]

  90 days

• Average concentration-to-dose ratio of FK during the first 90 days post transplantation [days 3, 7, 14±3, 30±3, 60+±3, 90±3 days post transplantation]

  90 days

• Time to reach the first target FK range

  90 days

• Number of FK dose adjustments required to reach the target FK level

  90 days

Study Arms (2)

Intervention genotyping group

EXPERIMENTAL

Patients who are scheduled to receive renal transplant from a living donor between January 2021 to January 2023. They will be assigned to receive the initial CYP3A5 genotype-based tacrolimus (FK) dose as determined by their CYP3A5 genotype. CYP3A5 expresser (extensive or intermediate metabolizer) - 0.20mg/kg CYP3A5 non-expresser (poor metabolizer) - 0.15mg/kg The starting dose of the intervention arm will be reviewed for every 10 patients recruited based on the drug levels achieved.

Drug: Tacrolimus

Historical Control Group

NO INTERVENTION

Patients who received renal transplant from a living donor between January 2016 - December 2020 and received standard weight-based dosing of tacrolimus

Interventions

Tacrolimus DRUG

Starting dose based on CYP3A5 genotype

Intervention genotyping group

Eligibility Criteria

• Age: 21 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• On follow up at SGH between the ages of 21 and 75 years old who had received or are scheduled to receive a living donor renal transplant between January 2016 to January 2023
• Has to receive tacrolimus (FK) (Prograf®; Astellas Pharma, Singapore), mycophenolic acid (MPA) (Cellcept®; Roche, Basel, Switzerland or Myfortic®; Novartis Pharma AG, Basel, Switzerland) and prednisolone as triple immunosuppressive drug maintenance regimen

You may not qualify if:

• Planned to be initiated on non-standard doses of tacrolimus (e.g. planned to initiate on sub-therapeutic doses of tacrolimus)
• Evidence of active liver disease or gastrointestinal disorder that might interfere with the ability to absorb oral medication
• Contraindications to tacrolimus (FK) - e.g. hypersensitivity
• Takes concurrent medications which are known to severely interact with FK (e.g. verapamil, azoles, rifampicin, erythromycin or clarithromycin

Sponsors & Collaborators

• Singapore General Hospital: lead

Study Sites (1)

Singapore General Hospital

Singapore, 767972, Singapore

Location

Related Publications (3)

• Shuker N, Bouamar R, van Schaik RH, Clahsen-van Groningen MC, Damman J, Baan CC, van de Wetering J, Rowshani AT, Weimar W, van Gelder T, Hesselink DA. A Randomized Controlled Trial Comparing the Efficacy of Cyp3a5 Genotype-Based With Body-Weight-Based Tacrolimus Dosing After Living Donor Kidney Transplantation. Am J Transplant. 2016 Jul;16(7):2085-96. doi: 10.1111/ajt.13691. Epub 2016 Feb 26.

  PMID: 26714287 BACKGROUND

• Chen SY, Li JL, Meng FH, Wang XD, Liu T, Li J, Liu LS, Fu Q, Huang M, Wang CX. Individualization of tacrolimus dosage basing on cytochrome P450 3A5 polymorphism--a prospective, randomized, controlled study. Clin Transplant. 2013 May-Jun;27(3):E272-81. doi: 10.1111/ctr.12101. Epub 2013 Feb 24.

  PMID: 23432535 BACKGROUND

• Birdwell KA, Decker B, Barbarino JM, Peterson JF, Stein CM, Sadee W, Wang D, Vinks AA, He Y, Swen JJ, Leeder JS, van Schaik R, Thummel KE, Klein TE, Caudle KE, MacPhee IA. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015 Jul;98(1):19-24. doi: 10.1002/cpt.113. Epub 2015 Jun 3.

  PMID: 25801146 BACKGROUND

MeSH Terms

Interventions

Tacrolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single interventional group with historical control group

Study Record Dates

• First Submitted: March 26, 2021
• First Posted: April 1, 2021
• Study Start: February 1, 2021
• Primary Completion: January 16, 2024
• Study Completion: April 9, 2024
• Last Updated: November 13, 2024

Record last verified: 2024-11

Locations

SG (1)