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

Abstract

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.cpicp gx.org).

Functional interpretation, cataloging, and analysis of 1,341 known and new glucose-6-phosphate dehydrogenase variants

“…To further confound this, reports of activity and clinical presentation for one variant can vary greatly between individuals and over time. 4 The 2022 WHO classification system takes interindividual variation into account, requiring that classification is based on clinical reports of the presence or . CC-BY-NC 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

“…Activity measurements taken during a hemolytic crisis or following a transfusion can be elevated due to high percentages of reticulocytes or donor cells, and lack of that information can confound analysis of biobank data. 4 Reporting multiple measurements over time compared to nondeficient controls aids in interpretation of G6PD activity tests. 1,4 Our efforts to classify G6PD variants using published data benefited from the abundant literature, since G6PD deficiency was first described in 1956.…”

“…2 Individuals with G6PD deficiency have variants with decreased activity, which can lead to three main clinical manifestations: neonatal jaundice, chronic nonspherocytic hemolytic anemia (CNSHA), and acute hemolytic anemia (AHA) in response to stressors such as certain foods, antibiotics, antimalarials, and infections that elevate reactive oxygen species. 3,4 Underlying G6PD deficiency is great genetic diversity, with hundreds of identified variant alleles, mostly missense variants in the coding sequence. 1 Interpreting the function and clinical effects of G6PD variants is critical to prevent adverse drug reactions, which are avoidable by prescribing alternate drugs, and to promote neonatal health by prompting increased monitoring.…”

“…1 Interpreting the function and clinical effects of G6PD variants is critical to prevent adverse drug reactions, which are avoidable by prescribing alternate drugs, and to promote neonatal health by prompting increased monitoring. 3,5 The G6PD gene is located on the X chromosome, so variant phenotypes are most clearly observed in hemizygotes and homozygotes; heterozygotes are largely unaffected, though phenotypes vary between individuals and over time due to random X-inactivation 4 , but identification is important to avoid anemia and jaundice in hemizygous fetuses. 1,5 Some G6PD variants reach high frequency in specific populations since they provide protection from severe malarial infection and thus are under balancing selection.…”

“…9 The Clinical Pharmacogenetics Implementation Consortium (CPIC) recently released updated guidelines for medication use in G6PD-deficient individuals, including seven drugs with high risk of inducing AHA in G6PD-deficient patients. 4 To improve genetic assessment of G6PD deficiency and risk of AHA, we sought to collect all reports of G6PD variant activity measurements and clinical presentation. We also tested the implementation of the 2022 WHO classification system, and applied the American College of Medical Genetics (ACMG) clinical guidelines to incorporate data from multiple patients across studies to support clinical interpretation of G6PD variants.…”