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

利托那韦对哌替啶在HIV阴性人群药代动力学的影响

• 批准号: 6103662
• 负责人: STEPHEN PISCITELLI
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6103662
• 关键词: HIV infections; clinical research; combination chemotherapy; drug adverse effect; drug screening /evaluation; human subject; meperidine; pharmacokinetics; protease inhibitor; ritonavir

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.

人类免疫缺陷病毒（HIV）感染的患者可能需要给予哌替啶以控制疼痛或与白细胞介素-2或白介素B相关的寒战和寒战。利托那韦（Norvir）是一种蛋白酶抑制剂，是细胞色素P-450的强效抑制剂，细胞色素P-450是参与药物代谢的主要酶系统。利托那韦和哌替啶联合用药理论上可能导致哌替啶浓度增加和毒性，因此，禁忌同时使用。本研究将描述度冷丁及其主要代谢产物去甲度冷丁在8名HIV阴性健康患者中的药代动力学特征。受试者将在研究第0天接受50 mg剂量的哌替啶PO给药。将在48小时内采集系列样本，用于测定度冷丁和去甲度冷丁浓度。利托那韦将在第2天开始，并在5天内递增至500 mg BID剂量。利托那韦治疗共10天后，将再次给予50 mg哌替啶PO剂量，并在72小时内采集样本，同时在整个采样期内继续利托那韦治疗。将比较两组之间的最大血药浓度、达到最大血药浓度的时间、曲线下面积和清除率。本研究将提供接受利托那韦合并治疗的患者中哌替啶分布的数据。目前，受试者入组和研究已完成，数据正在分析中。结果：哌替啶的AUC在所有受试者中平均下降67？存在RTV时为4%（p<0.005）。去甲哌替啶的平均AUC增加了47%，表明诱导了肝脏代谢。RTV暴露量与500 mg BID剂量的既往报告相似，CL/F平均值为5.6 L/h。结论：伴随RTV，哌替啶AUC显著降低而非增加。基于这些发现，该组合的麻醉剂相关不良反应的风险似乎很小。提示在RTV治疗中哌替啶无禁忌症。本研究终止。