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Medical Director, Oncology Medical Affairs Roche Laboratories 340 Kingsland Street Nutley, New Jersey 07110-1199
Published Online, November 5, 2003. www.theannals.com, DOI 10.1345/aph.1C510a
Navari and Koeller failed to discuss the different ability of 5-HT3 receptor antagonists to block sodium and potassium channels in vitro at concentrations achievable with therapeutic doses.2 For example, the plasma concentration resulting from 40 µg/kg of granisetron (4 times higher than the Food and Drug Administration [FDA]-approved dose) is lower than the concentration that produces marked sodium channel blockade or human ether-a-go-go-related gene (HERG) channel blockage in vitro. In contrast, the maximum concentration of hydrodolasetron resulting from a 1.8-mg/kg injection of dolasetron (an FDA-approved dose)3 is within the range that inhibits sodium channel current in vitro.2 These data correlate with observations in clinical trials. In multiple clinical trials, including those referenced by Navari and Koeller, no statistically significant QTc prolongation has been reported with granisetron.2,4 As reviewed by Navari and Koeller, in multiple studies, statistically significant QTc prolongation has been observed with dolasetron even at the FDA-approved dose.
In several of the studies cited by Navari and Koeller, patients with heart failure, arrhythmias requiring medication, greater than first-degree heart block, cardiotoxicity due to cumulative doses of anthracyclines, and abnormal potassium or calcium concentrations were excluded. However, many cancer patients are elderly, have concomitant cardiovascular disease, or may take other medications that prolong the QTc interval. Drug–drug interactions may be important, as evidenced by the reduced clearance of hydrodolasetron with coadministration of atenolol.3 Genotype may be important: CYP2D6 genetic polymorphism may result in reduced clearance of 5-HT3 receptor antagonists and other drugs that involve CYP2D6 metabolism administered to oncology patients.5,6 Other factors also may prolong the QTc interval including gender, alcoholism, and electrolyte imbalance. Some of these issues have been recognized in the FDA labeling of dolasetron that urges precaution when administering dolasetron to certain patients.3
We argue that, in clinical practice, QTc prolongation with 5-HT3 receptor antagonists should be considered less of a "class effect" and more a "dose effect." These drugs block sodium and HERG channels to different extents in vitro.2 Extensive published data show that dolasetron has a greater effect on QTc interval prolongation than ondansetron and granisetron. Statistically significant QTc prolongation has never been reported in the literature with granisetron. It is not disputed that 5-HT3 receptor antagonists have marked clinical benefit. However, several agents from this class are available. Therefore, when choosing a 5-HT3 receptor antagonist in a patient with a potential for electrolyte disturbance, receiving high-dose anthracycline therapy, taking other medications known to prolong the QTc interval, or with other factors that may prolong the QTc interval, it would seem prudent to use an effective 5-HT3 receptor antagonist that also has the least effect on sodium/HERG channels/QTc interval at a therapeutic dose, such as granisetron.
References
Related articles in The Annals:
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