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Background <p>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.</p> Methods <p>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.</p> Results <p>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&#xa0;and&#xa0;normal metabolizers (IMs&#xa0;and&#xa0;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&#xa0;and&#xa0;NMs were predicted to require a 100% dose increase relative to CYP3A5 PMs.</p> Conclusions <p>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.</p> Clinical Trial Registration Number <p>Clinicaltrials.gov NCT04645667</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月12日

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  • Tyler C. Dunlap,
  • Jing Zhu,
  • Daniel L. Weiner,
  • Ryan M. Kemper,
  • Susanna C. DeVane,
  • Feiyun Ma,
  • Veronica Nguyen,
  • James M. Coghill,
  • Viet Dang,
  • Tatjana Grgic,
  • Katarzyna Jamieson,
  • Jordan Miller,
  • Jennifer Myers,
  • Tejendra Patel,
  • Marcie Riches,
  • Jonathan S. Serody,
  • Morgan Trepte,
  • Benjamin G. Vincent,
  • William A. Wood,
  • Jonathan R. Ptachcinski,
  • J. Ryan Shaw,
  • Eric Weimer,
  • Paul M. Armistead,
  • Daniel J. Crona

摘要

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