PHARMACOKINETICS OF ORAL AND INTRAVENOUS DOLASETRON MESYLATE IN PATIENTS WITH RENAL IMPAIRMENT

In an open-label, randomized, two-way complete crossover study, the in fluence of renal impairment on the pharmacokinetics of dolasetron and its primary active metabolite, hydrodolasetron, were evaluated. Patien ts with renal impairment were stratified into thr ee groups of 12 base d on their 24-hour creatinine clearance (Cl-cr): group 1, mild impairm ent (Cl-cr between 41 and 80 ml/min); group 2, moderate impairment (Cl -cr between 11 and 40 ml/min); and group 3, endstage renal impairment (Cl-cr less than or equal to 10 mL/min). Twenty-four healthy volunteer s from a previous study served as the control group. Each participant received a single intravenous or oral 200-mg dose of dolasetron mesyla te on separate occasions. Serial blood samples were collected up to 60 hours after dose for determination of dolasetron and hydrodolasetron, and urine samples were collected in intervals up to 72 hours for dete rmination of dolasetron, hydrodolasetron, and the 5' and 6'-hydroxy me tabolites of hydrodolasetron. Because plasma concentrations were low a nd sporadic, pharmacokinetic parameters of dolasetron were not calcula ted after oral administration. Although some significant differences i n area under the concentration-time curve (AUC(0-infinity)), volume of distribution (Vd), systemic clearance (Cl), and elimination half-life (t(1/2)) of the parent drug were observed between control subjects an d patients with renal impairment, there were no systematic findings re lated to degree of renal dysfunction. The elimination pathways of hydr odolasetron include both hepatic metabolism and renal excretion. Consi stent increases in mean C-max, AUC(0-infinity), and t(1/2) and decreas es in renal and fetal apparent clearance of hydrodolasetron were seen with diminishing renal function after intravenous administration of do lasetron mesylate. No consistent changes were found after oral adminis tration. Urinary excretion of hydrodolasetron and its metabolites decr eased with decreasing renal function, but the profile of metabolites r emained constant. Dolasetron was well tolerated in all three groups of patients. Based on these findings, no dosage adjustment for dolasetro n is recommended in patients with renal impairment. Journal of Clinica l Pharmacology, 1998;38:798-806 (C) 1998 The American College of Clini cal Pharmacology.