Pharmacokinetics of Ondansetron in Patients with Hepatic Insufficiency

Abstract

Ondansetron is primarily eliminated via hepatic metabolism; thus, liver disease may affect its clearance. The pharmacokinetics of ondansetron in patients with different degrees of hepatic insufficiency (N = 12 with hepatic impairment, as categorized by Pugh's classification method) were assessed and the results compared with results for age- and gender-matched control subjects with normal liver function (n = 12). A secondary objective was to correlate the Pugh method of assessing hepatic impairment and quantitative metabolic markers used to assess hepatic function (antipyrine clearance and indocyanine green clearance) with changes in the pharmacokinetics of ondansetron. This was an open-label study in which 8 mg ondansetron was given orally and intravenously, following a randomized crossover design. Clearance of ondansetron was lower among patients with hepatic impairment that control subjects. After a single, oral dose of ondansetron, mean absolute bioavailability increased markedly with increased hepatic insufficiency (approaching 100% in the group with severe hepatic impairment versus 66% for control subjects). These data suggest that there is a reduced first-pass effect in patients with liver disease resulting in a higher AUC0-infinity. A correlation existed between clearance of ondansetron and decreased antipyrine clearance; a smaller correlation existed between ondansetron clearance and indocyanine green clearance. Mean percent of ondansetron bound to plasma proteins was significantly lower in patients with liver disease than in control subjects. None of the patients experienced any severe adverse reactions attributed to ondansetron. A reduction in the clearance of ondansetron is associated with increasing degrees of hepatic insufficiency; therefore, patients with severe hepatic impairment (Pugh score of > 9) should have their daily dose of ondansetron limited to 8 mg (or 0.15 mg/kg).

Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study

“…Ondansetron is primarily eliminated via hepatic oxidative metabolism of the indole moiety; thus liver disease may affect its clearance and it has been shown that a progressive decline in systemic clearance of ondansetron occurred with increased severity of liver disease. 27 Although a pharmacological survey was not performed in this study, it is uncertain whether the durable effect of ondansetron on fatigue was related to delayed hepatic clearance of the drug. Indeed, the half life of the drug is approximately three hours, all of our patients had compensated liver disease without cirrhosis (see table 1), and the daily doses of ondansetron (that is, 8 mg orally) administered in the present study were safe in such conditions.…”

“…Indeed, the half life of the drug is approximately three hours, all of our patients had compensated liver disease without cirrhosis (see table 1), and the daily doses of ondansetron (that is, 8 mg orally) administered in the present study were safe in such conditions. 27 Further studies are required to explore the underlying mechanism of the 5-HT 3 receptor antagonist on fatigue in humans. Thus an important question is whether ondansetron mediates this behavioural effect.…”

Oral, subcutaneous, and intravenous pharmacokinetics of ondansetron in healthy cats

“…Due to the low percentage of renal excretion it is unlikely that drug pharmacokinetics are affected by renal disease to the extent that dose alteration is necessary (Roila & Del Favero, 1995; Simpson & Hicks, 1996), which was supported by a previous study assessing ondansetron administration in human systemic lupus erythematosis patients (Amantea et al , 1993). In humans, hepatic impairment does however result in increased bioavailability and AUC, likely due to a decrease in first-pass effect, as well as decreased clearance due to hepatic metabolism with subsequent prolongation in t 1/2 λ (Figg et al , 1996). Thus, further study is needed to determine the effects of age, renal, and hepatic impairment on ondansetron pharmacokinetics in cats to better tailor dosing to individual patients.…”

Palliation and Liver Failure: Palliative Medications Dosage Guidelines

“…32 Reduced clearance of ondansetron was shown to be associated with increasing degrees of hepatic insufficiency, therefore, it has been recommended that patients with severe hepatic impairment have their daily dose of this drug limited to 8 mg. 33 …”