Genotype-Guided Hydralazine Therapy

Background: Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity. Summary: There is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. Key Messages: NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension

Expanded Clinical Pharmacogenetics Implementation Consortium Guideline for Medication Use in the Context of G6PD Genotype

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia in the setting of oxidative stress, which can be caused by medication exposure. Regulatory agencies worldwide warn against the use of certain medications in persons with G6PD deficiency, but in many cases, this information is conflicting, and the clinical evidence is sparse. This guideline provides information on using G6PD genotype as part of the diagnosis of G6PD deficiency and classifies medications that have been previously implicated as unsafe in individuals with G6PD deficiency by one or more sources. We classify these medications as high, medium, or low to no risk based on a systematic review of the published evidence of the gene-drug associations and regulatory warnings. In patients with G6PD deficiency, high-risk medications should be avoided, medium-risk medications should be used with caution, and low-to-no risk medications can be used with standard precautions, without regard to G6PD phenotype. This new document replaces the prior Clinical Pharmacogenetics Implementation Consortium guideline for rasburicase therapy in the context of G6PD genotype (updates at: www.cpicpgx.org)

Multisite evaluation of institutional processes and implementation determinants for pharmacogenetic testing to guide antidepressant therapy.

There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best-worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx-guided pharmacotherapy for antidepressant management

Best–worst scaling methodology to evaluate constructs of the Consolidated Framework for Implementation Research: application to the implementation of pharmacogenetic testing for antidepressant therapy

Abstract Background Despite the increased demand for pharmacogenetic (PGx) testing to guide antidepressant use, little is known about how to implement testing in clinical practice. Best–worst scaling (BWS) is a stated preferences technique for determining the relative importance of alternative scenarios and is increasingly being used as a healthcare assessment tool, with potential applications in implementation research. We conducted a BWS experiment to evaluate the relative importance of implementation factors for PGx testing to guide antidepressant use. Methods We surveyed 17 healthcare organizations that either had implemented or were in the process of implementing PGx testing for antidepressants. The survey included a BWS experiment to evaluate the relative importance of Consolidated Framework for Implementation Research (CFIR) constructs from the perspective of implementing sites. Results Participating sites varied on their PGx testing platform and methods for returning recommendations to providers and patients, but they were consistent in ranking several CFIR constructs as most important for implementation: patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and identification of champions. Conclusions This study demonstrates the feasibility of using choice experiments to systematically evaluate the relative importance of implementation determinants from the perspective of implementing organizations. BWS findings can inform other organizations interested in implementing PGx testing for mental health. Further, this study demonstrates the application of BWS to PGx, the findings of which may be used by other organizations to inform implementation of PGx testing for mental health disorders.http://deepblue.lib.umich.edu/bitstream/2027.42/174087/1/43058_2022_Article_300.pd