Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients

• Published in: Clinical and translational science 2021-05, Vol.14 (3), p.908-918
• Main Authors: Zhu, Jing, Campagne, Olivia, Torrice, Chad D., Flynn, Gabrielle, Miller, Jordan A., Patel, Tejendra, Suzuki, Oscar, Ptachcinski, Jonathan R., Armistead, Paul M., Wiltshire, Tim, Mager, Donald E., Weiner, Daniel L., Crona, Daniel J.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aged; Biological Variation, Population; Bone marrow; Calcineurin; Calcineurin inhibitors; Calcineurin Inhibitors - administration & dosage; Calcineurin Inhibitors - pharmacokinetics; Computer Simulation; Dosage; Dose-Response Relationship, Drug; Drug dosages; Female; Genetic testing; Genotype & phenotype; Graft vs Host Disease - immunology; Graft vs Host Disease - prevention & control; Graft-versus-host reaction; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic stem cells; Histocompatibility antigen HLA; Humans; Kidney transplantation; Kidney Transplantation - adverse effects; Kidney transplants; Male; Mass spectrometry; Metabolism; Middle Aged; Models, Biological; Patients; Pharmacokinetics; Phosphatase; Population studies; Proteins; Scientific imaging; Simulation; Single-nucleotide polymorphism; Stem cell transplantation; Stem cells; Tacrolimus; Tacrolimus - administration & dosage; Tacrolimus - pharmacokinetics; Transplantation Conditioning - methods; Young Adult
• ISSN: 1752-8054; 1752-8062
• DOI: 10.1111/cts.12956

Tacrolimus is a calcineurin inhibitor used to prevent acute graft versus host disease in adult patients receiving allogeneic hematopoietic stem cell transplantation (HCT). Previous population pharmacokinetic (PK) models have been developed in solid organ transplant, yet none exists for patients receiving HCT. The primary objectives of this study were to (1) use a previously published population PK model in adult patients who underwent kidney transplant and apply it to allogeneic HCT; (2) evaluate model‐predicted tacrolimus steady‐state trough concentrations and simulations in patients receiving HCT; and (3) evaluate covariates that affect tacrolimus PK in allogeneic HCT. A total of 252 adult patients receiving allogeneic HCT were included in the study. They received oral tacrolimus twice daily (0.03 mg/kg) starting 3 days prior to transplant. Data for these analyses included baseline clinical and demographic data, genotype data for single nucleotide polymorphisms in CYP3A4/5 and ABCB1, and the first tacrolimus steady‐state trough concentration. A dosing simulation strategy based on observed trough concentrations (rather than model‐based predictions) resulted in 12% more patients successfully achieving tacrolimus trough concentrations within the institutional target range (5–10 ng/ml). Stepwise covariate analyses identified HLA match and conditioning regimen (myeloablative vs. reduced intensity) as significant covariates. Ultimately, a previously published tacrolimus population PK model in kidney transplant provided a platform to help establish a model‐based dose adjustment strategy in patients receiving allogenic HCT, and identified HCT‐specific covariates to be considered for future prospective studies. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Tacrolimus is a cornerstone immunosuppressant used in patients who undergo organ transplantations. However, because of its narrow therapeutic index and wide interpatient pharmacokinetic (PK) variability, optimizing its dose is crucial to maximize efficacy and minimize tacrolimus‐induced toxicities. Prior to this study, no tacrolimus population PK models have been developed for adult patients receiving allogeneic hematopoietic stem cell transplantation (HCT). Therefore, research effort was warranted to develop a population PK model that begins to propose more precision tacrolimus dosing and begins to address both a clinical and scientific gap in this patient population. WHAT QUESTION DID THIS STUD