Gupta S K, Kunka R L, Metz A, Lloyd T, Rudolph G, Perel J M
Department of Clinical Pharmacology, Glaxo Research Institute, Research Triangle Park, North Carolina 27709, USA.
J Clin Pharmacol. 1995 Feb;35(2):202-7. doi: 10.1002/j.1552-4604.1995.tb05012.x.
Alosetron is under clinical development for the treatment of schizophrenia. This study evaluated the effect of oral alosetron dosing on the pharmacokinetics of haloperidol, the latter being administered daily to 13 schizophrenic patients for 56 days. Alosetron 1 mg daily or placebo was given by random assignment for 2 weeks. After a two-week alosetron washout period (during which patients received placebo), patients received the alternate treatment for another two weeks. Serial blood samples were collected for high-performance liquid chromatography determination of plasma haloperidol, reduced haloperidol, and alosetron at selected times for 24 hours after administration of haloperidol and alosetron on study days 21 and 49. Mean pharmacokinetic parameters of haloperidol in the presence of alosetron and placebo treatments were not significantly (P > .05) different: dose-normalized Cmax (6.40 versus 5.75 ng/mL), dose-normalized Cmin (2.00 versus 1.90 ng/mL), dose-normalized 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 dosing. The model confirmed that there was no change in the pharmacokinetics of haloperidol when alosetron was administered concomitantly. Mean AUC ratios of reduced haloperidol to haloperidol (0.18) in the presence of alosetron were similar to values obtained in the absence of alosetron, indicating that alosetron had no influence on the metabolism of haloperidol. Mean pharmacokinetic parameters of alosetron were similar to those in previous studies in healthy subjects.
阿洛司琼正处于治疗精神分裂症的临床开发阶段。本研究评估了口服阿洛司琼给药对氟哌啶醇药代动力学的影响，后者每天给予13名精神分裂症患者，持续56天。通过随机分配给予阿洛司琼1mg/天或安慰剂，持续2周。在为期两周的阿洛司琼洗脱期（在此期间患者接受安慰剂）后，患者接受替代治疗另外两周。在研究第21天和第49天给予氟哌啶醇和阿洛司琼后24小时的选定时间，采集系列血样用于高效液相色谱法测定血浆氟哌啶醇、还原氟哌啶醇和阿洛司琼。在阿洛司琼和安慰剂治疗存在的情况下，氟哌啶醇的平均药代动力学参数无显著差异（P>0.05）：剂量标准化的Cmax（6.40对5.75ng/mL）、剂量标准化的Cmin（2.00对1.90ng/mL）、剂量标准化的AUC（85.97对68.48ng.hr/mL）和CL/f（78.23对104.7L/hr）。使用二室模型评估多次给药后氟哌啶醇的浓度和时间非依赖性药代动力学。该模型证实，同时给予阿洛司琼时氟哌啶醇的药代动力学没有变化。在存在阿洛司琼的情况下，还原氟哌啶醇与氟哌啶醇的平均AUC比值（0.18）与在不存在阿洛司琼的情况下获得的值相似，表明阿洛司琼对氟哌啶醇的代谢没有影响。阿洛司琼的平均药代动力学参数与先前在健康受试者中的研究相似。
