Tropisetron

Tropisetron (brand name Navoban) is a selective serotonin 5-HT3 receptor antagonist used primarily to prevent nausea and vomiting associated with chemotherapy and surgery.

It is indicated for the prevention of acute nausea and vomiting in patients undergoing emetogenic chemotherapy, as well as postoperative nausea and vomiting.

Tropisetron works by blocking serotonin (5-HT3) receptors both centrally in the chemoreceptor trigger zone and peripherally on vagal nerve terminals, thereby inhibiting the emetic signaling pathways.

The primary gene relevant to tropisetron response is CYP2D6, a member of the cytochrome P450 enzyme family. CYP2D6 is responsible for metabolizing tropisetron into less active compounds in the liver. Metabolism refers to the chemical processes that transform a drug into forms that can be eliminated from the body.

Genetic variations in CYP2D6 result in different metabolizer phenotypes: ultrarapid, normal, intermediate, or poor. These differences in enzyme activity affect how quickly tropisetron is cleared, which can influence drug levels, efficacy, and the risk of side effects.

CYP2D6 metabolizer status influences plasma levels of tropisetron and subsequent antiemetic response. Ultrarapid metabolizers clear the drug faster, potentially reducing effectiveness and increasing breakthrough nausea risk, whereas poor metabolizers may have higher exposure, which could enhance efficacy but also raise the chance of adverse effects like headache or constipation.

Ultrarapid Metabolizer

• Effect on drug levels: Increased metabolism leads to lower plasma concentrations.
• Clinical consequence: Reduced antiemetic efficacy; higher risk of breakthrough nausea and vomiting.
• Side effects: Fewer common side effects (headache, constipation) may occur less frequently due to lower drug exposure.

Normal Metabolizer

• Effect on drug levels: Expected plasma concentrations within typical therapeutic range.
• Clinical consequence: Standard efficacy in preventing nausea and vomiting.
• Side effects: Common side effects such as headache and constipation occur at expected frequencies (mild to moderate).

Intermediate Metabolizer

• Effect on drug levels: Slightly reduced metabolism, potentially modestly increased plasma concentrations.
• Clinical consequence: Generally effective antiemetic response; no significant changes expected.
• Side effects: Side effects similar to normal metabolizers; mild headache or constipation may occur.

Poor Metabolizer

• Effect on drug levels: Markedly reduced metabolism leads to higher plasma concentrations.
• Clinical consequence: Potentially enhanced efficacy, but also increased risk of dose-related adverse effects.
• Side effects: Increased likelihood of headache and constipation, typically mild to moderate in severity.

Indeterminate/Not available

• Effect: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.

CYP2D6 Dosing Guideline

Examples of alternative antiemetic drugs not primarily metabolized by CYP2D6 include granisetron.

• CPIC – Guideline for Ondansetron and Tropisetron and CYP2D6 Genotype