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. 2025 Aug 12.
doi: 10.1007/s40262-025-01529-w. Online ahead of print.

A Tacrolimus Population Pharmacokinetic Model for Adult Allogeneic Hematopoietic Cell Transplant Recipients Provides Clinical Opportunities for Precision Dosing

Tyler C Dunlap #  1 , Jing Zhu #  1 , Daniel L Weiner  1 , Ryan M Kemper  1 , Susanna C DeVane  1 , Feiyun Ma  1 , Veronica Nguyen  1 , James M Coghill  2   3   4 , Viet Dang  1 , Tatjana Grgic  2   5   6 , Katarzyna Jamieson  2   3   4 , Jordan Miller  5   6 , Jennifer Myers  2   7 , Tejendra Patel  1 , Marcie Riches  2   3   4 , Jonathan S Serody  2   3   4   8   9 , Morgan Trepte  2   5   6 , Benjamin G Vincent  2   3   4   8   9 , William A Wood  2   3   4 , Jonathan R Ptachcinski  2   5   6 , J Ryan Shaw  2   5   6 , Eric Weimer  10 , Paul M Armistead  2   3   4 , Daniel J Crona  11   12   13
Affiliations

A Tacrolimus Population Pharmacokinetic Model for Adult Allogeneic Hematopoietic Cell Transplant Recipients Provides Clinical Opportunities for Precision Dosing

Tyler C Dunlap et al. Clin Pharmacokinet. .

Abstract

Background: Tacrolimus is a cornerstone of acute graft-versus-host disease (aGVHD) prophylaxis in allogeneic hematopoietic cell transplant (allo-HCT) recipients. However, a narrow therapeutic index and high interindividual variability in pharmacokinetics (PK) make starting dose selection a major challenge in clinical practice.

Methods: Data from two PK studies conducted at the University of North Carolina Medical Center (UNCMC) were used to develop an oral tacrolimus population pharmacokinetic (popPK) model specific to adult allo-HCT recipients. Monte Carlo simulations were performed to compare the likelihood of achieving the UNCMC institutional target trough concentration range (ITR) (5-10 ng/mL) on the day of transplant (D0) under the current institutional dosing protocol, dosing recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC), and model-derived dosing recommendations.

Results: In total, 290 allo-HCT recipients contributed a total of 906 PK samples to the final analysis. A two-compartment popPK model adequately described the PK data. Population typical values of apparent clearance (TVCL/F) for 70 kg individuals receiving reduced intensity conditioning were 0.33 L/h/kg for CYP3A5 poor metabolizers (PMs) and 0.70 L/h/kg for intermediate and normal metabolizers (IMs and NMs). The probability of the population-level average D0 trough concentration being within the UNCMC ITR under the current UNCMC weight-based dosing protocol, CPIC-based, and model-derived dosing strategies were estimated to be 37%, 45%, and 76%, respectively. CYP3A5 IMs and NMs were predicted to require a 100% dose increase relative to CYP3A5 PMs.

Conclusions: We propose a new oral tacrolimus dosing strategy for adult allo-HCT recipients, which suggests the current weight-based dosing paradigm is insufficient. This new strategy includes CYP3A5 metabolizer phenotypes and conditioning regimen intensity, and could increase the percentage of allo-HCT recipients achieving target concentrations on D0.

Clinical trial registration number: Clinicaltrials.gov NCT04645667.

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Conflict of interest statement

Declarations. Funding: Dr. Dunlap was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM086330. Dr. Zhu was supported by the NHLBI under award number T32HL007148. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conflict of Interest: Dr. Weiner is an independent member of the Board of Directors and a member of the Scientific Advisory Board for Simulations Plus (Nasdaq:SLP). All other authors report no conflicts of interest related to this research. At the time of study conception and execution, Dr. Dunlap, Dr. Zhu, Dr. DeVane, Dr. Nguyen, Dr. Patel, Dr. Riches, and Dr. Ptachcinski were all employed at the University of North Carolina. However, currently Dr. Dunlap is employed by Metrum Research Group, Dr. Zhu by Pfizer, Dr. DeVane by Immatics, Dr. Nguyen by Biogen, Dr. Patel by Bristol Myers Squibb, Dr. Riches by Kura Oncology, and Dr. Ptachcinski by Johnson & Johnson. Ethics approval: All research activities were performed in accordance with the ethical standards of the responsible committee on human experimentation or with the Helsinki Declaration of 1975. Both studies =received approval from the University of North Carolina Institutional Review Board (UNC IRB) prior to subject enrollment and data collection (UNC16-1480 and UNC19-3328). UNC16-1480 was originally approved on July 21, 2016, and UNC19-3328 was originally approved on June 16, 2020. Both studies were renewed in 2025 by the UNC IRB. Consent: All research subjects from both studies (UNC16-1480 and UNC19-3328) provided informed consent to participate in their respective studies, for their genetic material to be used in our pharmacogenetics experiments and in the pharmacometric modeling and simulation, and all subjects provided consent to publish study results. Data Sharing Statement: Deidentified individual data that supports the results will be shared beginning 9–36 months following publication, provided the investigator who proposes to use the data has approval from an institutional review board (IRB), independent ethics committee (IEC), or research ethics board (REB), as applicable, and executes a data use/sharing agreement with UNC. Author contributions: Designed research—T.C.D., D.Z., J.R.P., P.M.A., D.L.W., and D.J.C. Performed research—all authors. Analyzed data—T.C.D., D.Z., D.L.W., R.M.K., and D.J.C. Wrote manuscript—all authors. Approved content for publication—all authors. Contributed new reagents/analytical tools—NA. Code availability: NONMEM control stream is in the supplemental.

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References

    1. Majhail NS, Farnia SH, Carpenter PA, Champlin RE, Crawford S, Marks DI, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2015;21:1863–9. https://doi.org/10.1016/j.bbmt.2015.07.032 . - DOI - PubMed - PMC
    1. Malard F, Holler E, Sandmaier BM, Huang H, Mohty M. Acute graft-versus-host disease. Nat Rev Dis Prim. 2023;9:27. https://doi.org/10.1038/s41572-023-00438-1 . - DOI - PubMed
    1. Ramachandran V, Kolli SS, Strowd LC. Review of graft-versus-host disease. Dermatol Clin. 2019;37:569–82. https://doi.org/10.1016/j.det.2019.05.014 . - DOI - PubMed
    1. Jacobson P, Uberti J, Davis W, Ratanatharathorn V. Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation. Bone Marrow Transplant. 1998;22:217–25. https://doi.org/10.1038/sj.bmt.1701331 . - DOI - PubMed
    1. Przepiorka D, Saliba R, Cleary K, Fischer H, Tonai R, Fritsche H, et al. Tacrolimus does not abrogate the increased risk of acute graft-versus-host disease after unrelated-donor marrow transplantation with allelic mismatching at HLA-DRB1 and HLA-DQB1. Biol Blood Marrow Transplant. 2000;6:190–7. https://doi.org/10.1016/s1083-8791(00)70042-5 . - DOI - PubMed

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