Palonosetron (DB00377): A Comprehensive Monograph on a Second-Generation 5-HT3 Receptor Antagonist

1.0 Executive Summary

Palonosetron is a second-generation serotonin 5-HT3 receptor antagonist distinguished by a unique pharmacological profile and superior clinical efficacy in the prevention of nausea and vomiting, particularly those induced by chemotherapy (CINV) and surgery (PONV). Chemically defined as the pure (S,S)-stereoisomer of a complex isoquinoline derivative, its structure confers a significantly higher binding affinity for the 5-HT3 receptor and facilitates unique allosteric interactions, which are not observed with first-generation agents like ondansetron or granisetron. These pharmacodynamic properties, combined with its exceptionally long pharmacokinetic half-life of approximately 40 hours, provide the basis for its sustained antiemetic activity.

Clinically, Palonosetron is the only 5-HT3 receptor antagonist monotherapy approved by the U.S. Food and Drug Administration (FDA) for the prevention of delayed CINV associated with moderately emetogenic chemotherapy (MEC). Pivotal clinical trials have consistently demonstrated its superiority over first-generation antagonists in providing a complete response—defined as no emesis and no rescue medication—over a 120-hour period. Its efficacy is well-established for acute CINV following both MEC and highly emetogenic chemotherapy (HEC), for PONV prevention up to 24 hours, and in pediatric populations as young as one month of age. Palonosetron serves as a foundational component in modern antiemetic regimens, where its efficacy is enhanced by co-administration with corticosteroids and neurokinin-1 (NK-1) receptor antagonists. This has led to its inclusion in guideline-recommended triple-therapy regimens and its development as part of a fixed-dose combination product, Akynzeo (palonosetron/netupitant).