THE EFFECT OF RITONAVIR ON THE PHARMACOKINETICS OF MEPERIDINE IN HIV-NEGATIVE SUB

人类免疫缺陷病毒（HIV）感染的患者可能需要给予哌嗪来控制与白细胞介素-2或两性霉素b相关的疼痛或寒战和僵硬。利托那韦（诺韦）是一种蛋白酶抑制剂，是细胞铬P-450的有效抑制剂，细胞铬P-450是参与药物代谢的主要酶系统。利托那韦与哌哌啶合用理论上可能导致哌啶浓度增加和毒性增加，因此，两者合用是禁忌的。本研究将在8名hiv阴性的健康患者中表征艾哌啶及其主要代谢物非艾哌啶的药代动力学。受试者将在研究的第0天接受50mg剂量的PO哌替啶。将在48小时内抽取连续样品以测定哌替啶和非哌替啶浓度。利托那韦将在第2天开始，并在5天内逐步增加至500mg BID。在服用利托那韦10天后，将再次给予50mg PO剂量的哌嗪，并在72小时内收集样本，同时在采样期间继续服用利托那韦。比较两组之间的最大血水平、到达最大血水平的时间、曲线下面积和清除率。该研究将提供同时接受利托那韦治疗的患者对哌替啶处置的数据。目前已完成受试者入组和研究，正在进行数据分析。结果：所有受试者的哌嗪AUC平均下降67 ？4%存在RTV （p<0.005）。去甲哌啶的平均AUC增加了47%，表明它能诱导肝脏代谢。RTV暴露与先前报告的500mg BID剂量相似，CL/F平均为5.6 L/h。结论：随RTV的增加，哌哌啶的AUC明显降低而非升高。根据这些发现，这种组合产生与麻醉有关的不良反应的风险似乎很小。这表明在RTV治疗过程中，哌哌啶的禁忌症是不必要的。本研究终止。

Human immunodeficiency virus (HIV)-infected patients may require administration of meperidine for pain control or chills and rigors associated with interleukin-2 or amphotericin B. Ritonavir (Norvir) is a protease inhibitor that is a potent inhibitor of cyto-chrome P-450, the major enzyme system involved in drug metabolism. The combination of ritonavir and meperidine could theoretically lead to increased meperidine concentrations and toxicity, and thus, their concomitant administration is contraindicated. This study will characterize the pharmacokinetics of meperidine and its major metabolite, nor- meperidine, in eight HIV-negative, healthy patients. Subjects will receive a 50 mg dose of PO meperidine on day 0 of the study. Serial samples will be drawn over 48 hours for determination of meperidine and nor-meperidine concentrations. Ritonavir will be initiated on day 2 and escalated to a dose of 500 mg BID over 5 days. After a total of 10 days of ritonavir, a 50 mg PO dose of meperidine will again be administered and samples will be collected over 72 hours while continuing ritonavir through the sampling period. Maximum blood level, time to maximum blood level, area under the curve, and clearance will be compared between the two groups. The study will provide data on meperidine disposition in patients receiving concomitant ritonavir. Currently, subject enrollment and study has been completed and data are being analyzed. Results: The AUC of meperidine decreased in all subjects by a mean of 67 ? 4 percent in the presence of RTV (p<0.005). Normeperidine mean AUC was increased 47 percent suggesting induction of hepatic metabolism. RTV exposure was similar to previous reports with 500 mg BID doses, CL/F averaged 5.6 L/h. Conclusions: Meperidine AUC is significantly reduced not increased, by concomitant RTV. Based on these findings, the risk of narcotic-related adverse effects from this combination appears to be minimal. This suggests that contraindication of meperidine is not necessary during RTV therapy. This study is terminated.