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

Abstract

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. 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 STUDY ADDRESS? The study addressed whether there is value in utilizing the observed tacrolimus steady‐state trough concentrations from patients receiving allogeneic HCT within the context of a pre‐existing population PK model developed for kidney transplant. The study also addressed whether there are clinically relevant covariates specific to adult patients receiving allogeneic HCT. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Inclusion of a single steady‐state tacrolimus trough concentration is beneficial to model predictions. The dosing simulation strategy based o...

Evaluation of published population pharmacokinetic models to inform tacrolimus dosing in adult heart transplant recipients

“…This is regardless of: (i) the number of prior dosing occasions (1–3) included for model predictions; and (ii) concomitant azole antifungal use. While studies 11,61–66 have demonstrated an improvement in individual predicted tacrolimus concentration considerably by models with input of at least 1 prior tacrolimus concentration, this was not the case in the present study. Given that the evaluated models were developed from transplant recipient populations where concomitant azole antifungal use was either prohibited or uncommon, the models are anticipated to reasonably predict tacrolimus concentration in the setting of without concomitant azole antifungal therapy in comparison to with concomitant azole antifungal therapy.…”

“…Relevant models developed from nonheart transplant recipients were included for evaluation. This is because recent data indicate that tacrolimus models can be extrapolated across various organ transplant recipient populations 11,65 . Further, only 1 54 of 2 tacrolimus population pharmacokinetic models 52,54 that considered type of organ transplant, identified distinct differences in tacrolimus clearance between a liver and nonliver transplant recipient populations.…”

“…This is because recent data indicate that tacrolimus models can be extrapolated across various organ transplant recipient populations. 11,65 Further, only 1 54 of 2 tacrolimus population pharmacokinetic models 52,54 that considered type of organ transplant, identified distinct differences in tacrolimus clearance between a liver and nonliver transplant recipient populations. With increasing evidence, this suggests the potential for extrapolation of tacrolimus models across different organ transplant recipient populations.…”

Pharmacogenomic Prescribing Opportunities in Percutaneous Coronary Intervention and Bone Marrow Transplant Patients

“…1.7% [White], 2.5% [African-American]) [15], and to actual CYP3A5 phenotype results obtained and previously reported in the allo-HCT study population (EM: 0.9% [White], 13% [African-American]; IM: 19% [White], 67% [African-American]). [23] The projected number of PGx-guided medication interventions was calculated for each population by multiplying the actual observed frequency of medication use within each study population and the estimated population at-risk genotype or phenotype frequencies for each associated medication, as described. [15] Calculations were completed separately in African-American and in non-African-American patients (non-African American was defined as either White, a race other than White or African-American, or unknown race).…”

Insights and lessons learned from a prospective clinical pharmacology study in allogeneic hematopoietic stem cell transplant during the COVID‐19 pandemic

“…We repurposed a published tacrolimus PopPK model from kidney transplant recipients, and determined that their model described our sparse data well with a 10.3% mean absolute prediction error. 6 However, to develop a more robust tacrolimus PopPK model in adult allo‐HCT recipients, where we account for HCT‐specific covariates, we have initiated a prospective clinical pharmacology study with intense sampling of tacrolimus concentrations (ClinicalTrials.gov identifier NCT NCT04645667; UNC IRB 19‐3328). Previously, our group has also published associations between germline genetics, and both tacrolimus PKs and clinical outcomes.…”