PHARMACOKINETICS OF ONDANSETRON IN PATIENTS WITH HEPATIC INSUFFICIENCY

Ondansetron is primarily eliminated via hepatic metabolism; thus, live r disease may affect its clearance. The pharmacokinetics of ondansetro n in patients with different degrees of hepatic insufficiency (N = 12 with hepatic impairment, as categorized by Pugh's classification metho d) were assessed and the results compared with results for age- and ge nder-matched control subjects with normal liver function (n = 12). A s econdary objective was to correlate the Pugh method of assessing hepat ic impairment and quantitative metabolic markers used to assess hepati c function (antipyrine clearance and indocyanine green clearance) with changes in the pharmacokinetics of ondansetron, This was an open-labe l 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 than control subjects, Af ter a single, oral dose of ondansetron, mean absolute bioavailability increased markedly with increased hepatic insufficiency (approaching 1 00% in the group with severe hepatic impairment versus 66% for control subjects), These data suggest that there is a reduced first-pass effe ct in patients with liver disease resulting in a higher AUC(0-infinity ). A correlation existed between clearance of ondansetron and decrease d antipyrine clearance; a smaller correlation existed between ondanset ron clearance and indocyanine green clearance, Mean percent of ondanse tron bound to plasma proteins was significantly lower in patients with liver disease than in control subjects. None of the patients experien ced any severe adverse reactions attributed to ondansetron, A reductio n in the clearance of ondansetron is associated with increasing degree s of hepatic insufficiency; therefore, patients with severe hepatic im pairment (Pugh score of >9) should have their daily dose of ondansetro n limited to 8 mg (or 0.15 mg/kg).