Ondansetron, a 5-HT3 receptor agonist, is widely used to manage chemotherapy-induced nausea and vomiting (CINV), with varying degrees of success. Why does ondansetron seem to work better for some pediatric patients with cancer who experience CINV but not others?

Approximately 30% of patients are refractory to ondansetron, and previous research has shown that genomic differences may be partly responsible. This inspired a team of researchers to investigate if certain genetic variations were associated with ondansetron failure. They were specifically focused on genetic variations in the drug-metabolizing enzyme CYP2D6, the transporter ABCB1, and the receptor 5-HT3. Their findings were published in Supportive Care in Cancer.

The researchers recruited 103 patients who consented to participate in a study that used DNA samples from blood draws to genotype a series of polymorphisms. For this study, ondansetron failure was defined as when a standard regimen of ondansetron did not work for a patient, which was determined by a systematic review of the patient’s medical record and analysis of patient-reported outcomes.


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“Our findings demonstrated that the polymorphism rs45460698 on the 5-HT3RB gene was predictive of ondansetron failure in both the univariate and multivariate analysis, particularly in combination with rs1045642 on ABCB1 in multivariate analysis,” the researchers stated.

They also noted that their study incorporated a more diverse patient population in terms of race, diagnosis, and ethnicity compared with many previous studies. But that could also limit the conclusions that can be drawn. The study also had a small sample size.

These findings provide “preliminary information about the role of pharmacogenetics in metabolism of ondansetron and in management of (CINV) in pediatric patients,” and the researchers suggested future research should focus on some specific deletions, notably the deletions at rs45460698 on 5-HT3RB. Ultimately, they hope that patients at risk for ondansetron failure could be identified early and be switched to another 5-HT3 receptor agonist.

Reference

Jacobs SS, Dome JS, Gai J, et al. Pharmacogenetic and clinical predictors of ondansetron failure in a diverse pediatric oncology population. Supportive Care in Cancer. Published online January 11, 2022. doi:10.1007/s00520-022-06818-9