Prospective Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Transplant. Dec 18, 2023; 13(6): 368-378
Published online Dec 18, 2023. doi: 10.5500/wjt.v13.i6.368
Dosing strategies for de novo once-daily extended release tacrolimus in kidney transplant recipients based on CYP3A5 genotype
Adam Diamond, Sunil Karhadkar, Kenneth Chavin, Serban Constantinescu, Kwan N. Lau, Oscar Perez-Leal, Kerry Mohrien, Nicole Sifontis, Antonio Di Carlo
Adam Diamond, Kerry Mohrien, Department of Pharmacy, Temple University Hospital, Philadelphia, PA 19140, United States
Sunil Karhadkar, Kenneth Chavin, Kwan N. Lau, Antonio Di Carlo, Department of Surgery, Temple University Hospital, Philadelphia, PA 19140, United States
Serban Constantinescu, Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, United States
Oscar Perez-Leal, Department of Pharmaceutical Sciences, Jayne Haines Center for Pharmacogenomics and Drug Safety, Temple University School of Pharmacy, Philadelphia, PA 19140, United States
Nicole Sifontis, Department of Pharmacy Practice, Temple University School of Pharmacy, Philadelphia, PA 19140, United States
Author contributions: Diamond A and Di Carlo A participated in design and oversight of the study, data collection, data analysis, and drafted and finalized the manuscript; Karhadkar S and Lau KN, participated in design and oversight of the study, and assisted with data analysis; Chavin K drafted the manuscript and assisted with data analysis; Constantinescu S participated in design and oversight of the study, drafted the manuscript, and assisted with data analysis; Mohrien K performed statistical analysis in conjunction with Temple University Center for Biostatistics & Epidemiology, participated in data analysis, and drafted the manuscript; Perez-Leal O conducted DNA analysis for genotype samples and analyzed genotype data, and drafted the manuscript; Sifontis N participated in design and oversight of the study, assisted with data analysis, and drafted the manuscript; all authors read and approved the final manuscript.
Supported by Veloxis Pharmaceuticals, Inc. 1001 Winstead Drive Suite 310, Cary, NC 27513.
Institutional review board statement: The study was reviewed and approved by the institutional review board of Temple University (Philadelphia, PA, United States; Approval No. 25286).
Clinical trial registration statement: This clinical trial is registered with ClinicalTrials.gov, using identifier NCT03713645. Details can be found at https://classic.clinicaltrials.gov/ct2/show/NCT03713645.
Informed consent statement: All study participants, or their legal guardian, provided written consent prior to study enrollment.
Conflict-of-interest statement: Adam Diamond serves as an active member of the Veloxis Pharmaceuticals Speaker’s Bureau (honoraria provided).
Data sharing statement: There is no additional data available.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Sunil Karhadkar, FACS, MCh, MD, Associate Professor, Department of Surgery, Temple University Hospital, No. 3401 North Broad Street, Philadelphia, PA 19140, United States. sunilk@temple.edu
Received: August 30, 2023
Peer-review started: August 30, 2023
First decision: September 29, 2023
Revised: October 16, 2023
Accepted: October 26, 2023
Article in press: October 26, 2023
Published online: December 18, 2023
ARTICLE HIGHLIGHTS
Research background

Tacrolimus has been extensively studied and shown to require significant dose adjustments in CYP3A5 expressers compared to non-expressers. Data regarding the impact of CYP35 expresser status on the dosing of tacrolimus extended-release tablets has not been published and is important to understand given the vastly different pharmacokinetic profile of this tacrolimus formulation. There is an increased use of tacrolimus extended-release tablets in the de novo setting warranting further investigation into this clinical question.

Research motivation

The main concerns when initiating tacrolimus in the de novo kidney transplant setting is to achieve therapeutic tacrolimus trough concentrations in a reasonable timeframe while also avoiding drug toxicity. The rationale behind this research is to identify dosing strategies that should be considered when initiating tacrolimus extended-release immediately after kidney transplant. Particular, research evaluating dosing strategies in patients known to have higher tacrolimus dose requirements (i.e. CYP3A5 expressers) will provide data for transplant centers to make educated clinical decisions surrounding dosing and dosing adjustments for tacrolimus extended-release tablet formulations.

Research objectives

The main objectives of this research was to identify the time to therapeutic tacrolimus trough concentration as well as the dose required to obtain that trough concentration. These objectives were realized as well as the differences in dosing requirements amongst CYP3A5 expressers compared to non-expressers. The significance of these objectives warrant further investigation towards linking clinical outcomes such as acute rejection and graft function outside of the first month after transplant in patients receiving tacrolimus extended-release tablets in the de novo kidney transplant setting.

Research methods

Patients (n = 36) were consented to receive tacrolimus extended-release tablets at a dose of 0.13 mg/kg/d at the time of kidney transplantation. Dosing was adjusted to maintain therapeutic trough concentrations of 8-10 ng/mL which assisted in identifying the primary objective of time to therapeutic concentration. In addition, all patients that consented to CYP3A5 genotype testing (n = 34) were included in additional data analysis to describe dosing requirements for tacrolimus extended-release tablets in patients that were CYP3A5 expressers compared to CYP3A5 non-expressers. These methods allowed the authors to describe initial dosing requirements as well as the impact of CYP3A5 metabolism on tacrolimus extended-release dosing and attainment of target trough concentrations.

Research results

This research demonstrated that kidney transplant recipients who are expressers of CYP3A5 exhibited higher dose requirements for tacrolimus extended-release tablets and also experienced delays in attaining therapeutic trough concentrations compared to CYP3A5 non-expressers. These findings are pertinent to the field of solid organ transplant since transplant centers that utilize tacrolimus extended-release tablets in the de novo setting should be aware of the higher dosing needs in this patient population. In addition, transplant recipients suspected to or known to be CYP3A5 expressers may require more aggressive dose titration to achieve and maintain target tacrolimus trough concentrations. Future research in this area should focus on clinical outcomes beyond our study period of 30 d to determine the impact on acute rejection and kidney graft function.

Research conclusions

Overall, this study provides additional clinical information regarding the dosing requirements of tacrolimus extended-release tablets in the de novo kidney transplant setting. To our knowledge, this is the first prospective observational study to provide outcomes data for the de novo dosing of tacrolimus extended-release tablets. The findings from this research validate that the impact of CYP3A5 expression has a clinical impact on the pharmacokinetic profile of tacrolimus extended-release tablets similar to findings published with tacrolimus immediate-release. New approaches to dosing and dose titration for tacrolimus extended-release tablets have been proposed by this research in the de novo kidney transplant setting and can be used as a guide when making clinical decisions in this patient population.

Research perspectives

Future research should aim to randomize patients to various doses of tacrolimus extended-release tablets to offer a more advanced comparison of different initial dosing strategies. Conducting CYP3A5 genotype analyses prior to study drug initiation would be beneficial in future studies in order to further assess the impact of pharmacokinetic variations in metabolism on tacrolimus extended-release tablets.