We thank Hung and Chao1 for their interest in our study and their laudatory comments regarding the importance of the subject and the comprehensiveness of the analysis.2 In subgroup analyses, we found that patients using at least one other medication with known risk of Torsades de Pointes at the time of ondansetron initiation may have had a lower 10-day relative risk of sudden cardiac death compared with patients not using such medications at the time of ondansetron initiation. Small subgroup sample sizes limited a formal assessment of statistical interaction and also warrant caution when interpreting these findings. Hung and Chao propose that these unexpected findings, albeit exploratory in nature, may be attributable to a pharmacokinetic interaction. Specifically, they posit that coprescription of a proton pump inhibitor, a drug that induces hepatic 1A2 expression, could lessen the risk of sudden cardiac death by decreasing the serum concentration of ondansetron. We agree with the authors that this is a possible explanation for the finding. However, ondansetron is a substrate for multiple hepatic cytochrome P (CYP)-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In vitro studies suggest that, in the presence of an inhibitor for one metabolizing enzyme, the other metabolizing enzymes would compensate, resulting in minimal change to the rate of ondansetron elimination.3

Although it is unknown whether a drug–drug interaction may have influenced the subgroup findings in our antiemetic study, the importance of drug–drug interactions should not be underestimated. In a prior study, we showed the potential for drug–drug interactions to potentiate the risk of sudden cardiac death associated with initiation of QT-prolonging drugs in the hemodialysis population.3 In an analysis of 72,559 individuals receiving maintenance hemodialysis, we showed that existing use of proton pump inhibitors, competitive inhibitors of CYP 2C19, enhances the 1-year risk of sudden cardiac death associated with the initiation of citalopram or escitalopram (drugs with known risks of Torsades de Pointes).4 Taken together, Hung and Chao's hypothesis and our prior drug interaction research (1) emphasize the importance of a further study of drug–drug interactions in the hemodialysis population and (2) underscore the urgency of developing effective strategies for reducing polypharmacy and medication-related harms in this population.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at https://links.lww.com/JSN/E666.

Funding

J.E. Flythe: NHLBI Division of Intramural Research (R01 HL152034).

Author Contributions

Conceptualization: Jennifer E. Flythe, Michele Jonsson Funk, Sherin Ismail.

Funding acquisition: Jennifer E. Flythe.

Project administration: Jennifer E. Flythe.

Resources: Jennifer E. Flythe.

Supervision: Jennifer E. Flythe.

Writing – original draft: Jennifer E. Flythe.

Writing – review & editing: Michele Jonsson Funk, Sherin Ismail.

1. Hung K-C, Chao C-T. Pharmacokinetic issue may influence the perceived cardiac risk posed by ondansetron in patients undergoing chronic hemodialysis. J Am Soc Nephrol. 2024. 2. Ismail S, Funk MJ, Flythe JE. Ondansetron and the risk of sudden cardiac death among individuals receiving maintenance hemodialysis. J Am Soc Nephrol. 2024. doi:10.1681/ASN.0000000000000336 3. U.S. Food and Drug Administration. Ondansetron Package Insert. Structured Product Labeling. 2016. Accessed March 23, 2024. https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/73df79da-f362-4a1a-9373-e4d25377d0c4/spl-doc?hl=ondansetron#Section_12.3 4. Assimon MM, Pun PH, Al-Khatib SM, et al. Proton pump inhibitors may enhance the risk of citalopram- and escitalopram-associated sudden cardiac death among patients receiving hemodialysis. Pharmacoepidemiol Drug Saf. 2022;31(6):670–679. doi:10.1002/pds.5428