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, using identifier NCT03713645. Details can be found at
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:
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.
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
Processing time: 109 Days and 20.3 Hours

Tacrolimus extended-release tablets have been Food and Drug Administration-approved for use in the de novo kidney transplant population. Dosing requirements often vary for tacrolimus based on several factors including variation in metabolism based on CYP3A5 expression. Patients who express CYP3A5 often require higher dosing of immediate-release tacrolimus, but this has not been established for tacrolimus extended-release tablets in the de novo setting.


To obtain target trough concentrations of extended-release tacrolimus in de novo kidney transplant recipients according to CYP3A5 genotype.


Single-arm, prospective, single-center, open-label, observational study ( NCT03713645). Life cycle pharma tacrolimus (LCPT) orally once daily at a starting dose of 0.13 mg/kg/day based on actual body weight. If weight is more than 120% of ideal body weight, an adjusted body weight was used. LCPT dose was adjusted to maintain tacrolimus trough concentrations of 8-10 ng/mL. Pharmacogenetic analysis of CYP3A5 genotype was performed at study conclusion.


Mean time to therapeutic tacrolimus trough concentration was longer in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (6 d vs 13.5 d vs 4.5 d; P = 0.025). Mean tacrolimus doses and weight-based doses to achieve therapeutic concentration were higher in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (16 mg vs 16 mg vs 12 mg; P = 0.010) (0.20 mg/kg vs 0.19 mg/kg vs 0.13 mg/kg; P = 0.018). CYP3A5 extensive metabolizers experienced lower mean tacrolimus trough concentrations throughout the study period compared to CYP3A5 intermediate metabolizers and non-expressers (7.98 ng/mL vs 9.18 ng/mL vs 10.78 ng/mL; P = 0 0.008). No differences were identified with regards to kidney graft function at 30-d post-transplant. Serious adverse events were reported for 13 (36%) patients.


Expression of CYP3A5 leads to higher starting doses and incremental dosage titration of extended-release tacrolimus to achieve target trough concentrations. We suggest a higher starting dose of 0.2 mg/kg/d for CYP3A5 expressers.

Keywords: Immunosuppression, Kidney transplant, Dosing, Tacrolimus, Therapeutic drug monitoring, Genotype

Core Tip: In this single-arm, prospective, observational study we study once-daily, extended release tacrolimus dosing. Here we find that the expression of the cyctrochrome P450 enzyme, CYP3A5, is an important clinical factor to determine optimal dosage requirements after kidney transplantation. In kidney transplant recipients who express CYP3A5 activity, higher doses of extended-release tacrolimus are required to attain therapeutic trough concentrations. Delays in achieving therapeutic trough concentrations has been linked to increase rates of acute rejection which highlights the importance of this research in identifying dosing considerations for extended-release tacrolimus in the de novo kidney transplant setting.