Monday, May 1, 2023

CYP3A5 genotyping is a more accurate predictor of drug response than race alone

 A new paper in Journal of Clinical Pharmacology from a group at Indiana University [PMID:37042314] implemented genotyping for CYP3A5 in a kidney transplant center.

The team used CPIC guidelines for tacrolimus dosing based on CYP3A5 genotype.

Implementation included provider education and clinical decision support in the electronic medical record.

This study reinforces that CYP3A5 genotype is an important predictor of therapeutic tacrolimus trough concentrations. They demonstrate that CYP3A5 normal and intermediate metabolizers had fewer tacrolimus trough concentrations within the desired range post-transplantation and took longer to achieve therapeutic dose than poor metabolizers. While the authors note they were underpowered to measure outcomes, there was a trend towards transplant rejection or all-cause mortality within the first year of transplant based on CYP3A5 metabolizer phenotype.

The paper highlights how, despite the guidelines from CPIC being published in 2015, the FDA label still currently only has language around race-based dose adjustment rather than giving precise guidance based on genotype:

“The FDA drug label recommends higher starting doses in individuals of African ancestry, but only 70% of African Americans are normal/intermediate metabolizers. CYP3A5 normal/intermediate metabolizers are also found among whites and Asians (East Asian and Central/South Asian) at lower frequencies (14% and 44-55%, respectively).”

“Self-reported African American race is more closely associated with CYP3A5 expresser status than other self-reported race categories, but self-reported race is not an accurate surrogate for genotype.”

The discussion is a reminder that pharmacogenomics can play a key role in reducing bias and fulfilling personalized precision medicine.

“Equality and minimization of bias in healthcare has recently become prioritized by healthcare systems as recognition of racial bias has come to the forefront in many non-healthcare aspects of society”

“One dose standard protocols and using race as a surrogate for genotype can both potentiate racial disparities in tacrolimus dosing. Routine CYP3A5 genotyping is a more accurate predictor of drug response than race alone and deemphasizes race as a biological variable in clinical care”

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