PHARMACOKINETICS OF DOLASETRON AFTER ORAL AND INTRAVENOUS ADMINISTRATION OF DOLASETRON MESYLATE IN HEALTHY-VOLUNTEERS AND PATIENTS WITH HEPATIC-DYSFUNCTION

In previous studies, dolasetron was shown to have both renal and hepat ic elimination mechanisms. This study was conducted to determine the i mpact of varying degrees of hepatic dysfunction on the pharmacokinetic s and safety of dolasetron and its reduced metabolites. Seventeen adul ts were studied: six healthy volunteers (group I), seven patients with mild hepatic impairment (Child-Pugh class A; group II), and four pati ents with moderate to severe hepatic impairment (Child-Pugh class B or C1; group III). Single 150-mg doses of dolasetron mesylate were admin istered intravenously and orally, with a 7-day washout period separati ng treatments. After intravenous administration, no differences were o bserved between healthy volunteers and patients with hepatic impairmen t in maximum plasma concentration (C-max), areas under the plasma conc entration-time curve (AUC), or elimination half-life (t(1/2)) of intac t dolasetron. No significant differences were found in C-max, AUC, or apparent clearance (Cl-app) of hydrodolasetron, the primary metabolite of dolasetron. The mean t(1/2) increased from 6.87 hours in group I t o 11.69 hours in group III. After oral administration, Cl-app of hydro dolasetron decreased by 42%, and C-max increased by 18% in patients wi th moderate to severe hepatic impairment. There were less changes in p atients with mildly hepatic impairment. Total percentage of dose excre ted as metabolites was similar for healthy volunteers and patients wit h hepatic impairment, although urinary metabolite profiles differed sl ightly. Dolasetron was well tolerated and there were no apparent diffe rences in adverse effects between groups or treatments. Because hepati c impairment did not influence Cl-app of hydrodolasetron after intrave nous administration, and the range of plasma concentrations of hydrodo lasetron after oral administration was not different from those observ ed in healthy volunteers, dosage adjustments are not recommended for p atients with hepatic disease and normal renal function.