EFFECT OF ALOSETRON (A NEW 5-HT3 RECEPTOR ANTAGONIST) ON THE PHARMACOKINETICS OF HALOPERIDOL IN SCHIZOPHRENIC-PATIENTS

Alosetron is under clinical development for the treatment of schizophr enia. This study evaluated the effect of oral alosetron dosing on the pharmacokinetics of haloperidol, the latter being administered daily t o 13 schizophrenic patients for se days. Alosetron 1 mg daily or place bo was given by random assignment for 2 weeks. After a two-week aloset ron washout period (during which patients received placebo), patients received the alternate treatment for another two weeks. Serial blood s amples were collected for high-performance liquid chromatography deter mination of plasma haloperidol, reduced haloperidol, and alosetron at selected times for 24 hours after administration of haloperidol and al osetron on study days 21 and 49. Mean pharmacokinetic parameters of ha loperidol in the presence of alosetron and placebo treatments were not significantly (P > .05) different: dose-normalized C-max (6.40 versus 5.75 ng/mL), dose-normalized C-min (2.00 versus 1.90 ng/mL), dose-nor malized AUC (85.97 versus 68.48 ng.hr/ml), and CL/f (78.23 versus 104. 7 L/hr). A two-compartment model was used to assess the concentration- and time-independent pharmacokinetics of haloperidol after multiple d osing. The model confirmed that there was no change in the pharmacokin etics of haloperidol when alosetron was administered concomitantly. Me an AUC ratios of reduced haloperidol to haloperidol (0.18) in the pres ence of alosetron were similar to values obtained in the absence of al osetron, indicating that alosetron had no influence on the metabolism of haloperidol. Mean pharmocokinetic parameters of alosetron were simi lar to those in previous studies in healthy subjects.