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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

74 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-02-01

Study Completion Date

2024-04-09

Brief Summary

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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.

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Detailed Description

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Tacrolimus (FK) remains the cornerstone of maintenance immunosuppressants after renal transplantation. However, it is characterised by narrow therapeutic index and large inter-individual variability in its pharmacokinetics, particularly in the dose required to reach target trough blood concentrations. Among several factors investigated for their possible influence on tacrolimus pharmacokinetics, polymorphisms in genes coding for biotransformation enzymes (cytochrome P450 (CYP) isoenzymes 3A4 and 3A5) have received much attention. Exposure to FK correlates with the cytochrome P450 (CYP) 3A4 and CYP3A5 which are polymorphically expressed. This is in part explained by the presence of single-nucleotide polymorphisms (SNPs) in the CYP3A5 and CYP3A4 genes.

To date, renal transplant (RTx) recipients receive standard weight-based dosing of FK and therapeutic drug monitoring is employed for subsequent dose adjustment to ensure target FK concentration is attained. However, the current weight-based dosing strategies to guide the initial FK dosing have been poorly predictive of the actual FK dose required to attain therapeutic FK level. With the increased possibility of sub-therapeutic FK level during the early phase post renal transplantation, it puts them at a higher risk of developing acute rejection.

There has been increasing evidence to suggest the implementation of pre-transplantation genotyping to guide the initial FK dose to achieve target FK concentrations as quickly as possible. On the contrary, there are a few studies that report contradictory results of genotype-guided FK dosing as being useful in attainment of target therapeutic levels.

Given the differences in CYP3A5 genotype prevalence among races and the controversy in clinical benefits of such a pro-active dosage strategy, the impact of CYP3A5 genotype-guided dosing on clinical outcome remains to be answered, especially in the local multi-ethnic population. This pro-active approach may also sound promising for the local multi-ethnic population where majority of the renal transplant population are CYP3A5 expressers who may require a higher initial dose of FK based on genotyping profile.

Conditions

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Kidney Transplant Rejection Kidney Transplant; Complications

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

SINGLE_GROUP

Single interventional group with historical control group

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Participants

Study Groups

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Intervention genotyping group

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.

Group Type EXPERIMENTAL

Tacrolimus

Intervention Type DRUG

Starting dose based on CYP3A5 genotype

Historical Control Group

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

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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Tacrolimus

Starting dose based on CYP3A5 genotype

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* 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

Exclusion Criteria

* 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

Minimum Eligible Age

21 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No