AMBULATORY PERITONEAL DIALYSIS--PHARMACOKINETICS OF LAMIVUDINE IN HIV

门诊腹膜透析--拉米夫定在HIV中的药代动力学

• 批准号: 6415252
• 负责人: Paul R Bohjanen
• 金额: $ 29.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6415252
• 关键词: HIV infections; blood chemistry; clinical research; continuous ambulatory peritoneal dialysis; dosage; high performance liquid chromatography; human subject; lamivudine; oral administration; pharmacokinetics

Purpose: Lamivudine is a potent HIV reverse transcriptase inhibitor and is commonly used in combination with other drugs to treat patients infected with HIV. A growing number of HIV- infected patients also have severe renal failure and are undergoing continuous ambulatory peritoneal dialysis (CAPD). The effect of CAPD on elimination of lamivudine is currently unknown. The purpose of this study is to evaluate the effect of CAPD on the pharmcokinetics of lamivudine in order to make dosage recommendations. Methods: Four HIV-infected patients already receiving lamivudine who also have severe renal impairment and are undergoing CAPD will be enrolled in the study. Fourteen days prior to their admission to the Duke GCRC, each patient will begin taking lamivudine from the same lot as provided by the investigators at a dose of 150 mg per day. During this period, patients will continue their CAPD regimen and all other medications as usual. The patients will then be admitted to the Duke GCRC; in the morning of day one, a pre-dose lamivudine serum sample will be drawn and then 150 mg of lamivudine will be given orally. Post-dose serum lamivudine samples will be obtained at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours. During this 24 hour period, patients will continue their usual CAPD schedule (exchanges every six hours in most cases), and a sample of dialysate will be collected from each exchange to measure lamivudine levels. In the morning of day two, a pre-dose lamivudine level will again be drawn and a 150 mg dose of lamivudine will be given orally. Again, post-dose serum lamivudine samples will be obtained at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours, but during this 24 hour period the patients will not undergo CAPD. Lamivudine levels in serum and peritoneal dialysate samples will be determined using a validated HPLC assay by personnel from Glaxo Wellcome Inc. Lamivudine serum concentrations determined pre-dose and at various times post-dose will be used to determine pharmacokinetic paramaters including the minimum serum concentration (C-min), maximum serum concentration (C-max), area under the the serum concentration versus time curve (AUC), and terminal elimination half life (t-1/2). These parameters will be calculated for each patient in the presence and absence of CAPD and may be used to determine whether or not CAPD significantly influences elimination of lamivudine. Also, for each patient, lamivudine levels will be measured in peritoneal dialysate samples throughout a 24 hour period. If the amount of lamivudine eliminated in peritoneal fluid is significant, it would suggest that dose adjustment would be necessary in patients receiving CAPD. Finally, the C-min and C-max levels around the dose of lamivudine given given on hospital day one would be expected to represent steady state levels in patients undergoing CAPD. These levels can be compared to the 50% inhibitory concentration of lamivudine and may be useful for making dosage recommendations. Results: To date, five patients have been identified in the Raleigh/Durham area who are candidates for this study. Two patients have been screened and enrolled, and one of has completed the study protocol. The study is expected be completed within the next four months. Significance: Although this is a small study, it could potentially determine if CAPD significantly influences elimination of lamivudine and could provide information to make dosage recommendations.

目的：拉米夫丁是一种有效的HIV逆转录酶抑制剂，通常与其他药物结合使用以治疗感染HIV的患者。越来越多的艾滋病毒感染患者也患有严重的肾衰竭，并且正在接受连续的卧床腹膜透析（CAPD）。目前尚不清楚CAPD对消除拉米夫丁的影响。这项研究的目的是评估CAPD对拉米夫定药物的影响，以提出剂量建议。方法：这项研究将招募四名患有lamivudine的HIV感染患者，这些患者也会受到严重的肾功能障碍，并且正在接受CAPD。在入院GCRC之前的十四天，每位患者将开始以每天150毫克的剂量从相同的批次中服用lamivudine。在此期间，患者将像往常一样继续其CAPD方案和所有其他药物。然后，患者将被送入杜克GCRC；在第一天的早晨，将抽取剂量的lamivudine血清样品，然后口服150毫克的lamivudine。剂量血清lamivudine样品将在0.25、0.5、0.75、1、1.5、2、3、4、6、8、10、12、16和24小时获得。在这24小时内，患者将继续他们通常的CAPD时间表（大多数情况下每六个小时交换每六个小时），并从每次交换中收集透析液样本，以测量lamivudine水平。在第二天的早晨，将再次绘制前剂量的lamivudine水平，并口服150毫克的lamivudine。同样，剂量后血清lamivudine样品将在0.25、0.5、0.75、1.5、1.5、2、3、4、6、8、8、10、12、16和24小时获得，但在这24小时内，患者将不接受CAPD。 Lamivudine levels in serum and peritoneal dialysate samples will be determined using a validated HPLC assay by personnel from Glaxo Wellcome Inc. Lamivudine serum concentrations determined pre-dose and at various times post-dose will be used to determine pharmacokinetic paramaters including the minimum serum concentration (C-min), maximum serum concentration (C-max), area under the the serum concentration versus time curve （AUC）和末端消除半衰期（T-1/2）。在存在和不存在CAPD的情况下，将对每个患者计算这些参数，并可以用于确定CAPD是否显着影响消除lamivudine。同样，对于每个患者，在24小时内将在腹膜透析样品中测量lamivudine水平。如果在腹膜液中消除的lamivudine量很大，则表明接受CAPD的患者需要调整剂量。最后，在医院第一天给出的lamivudine剂量周围的C-MIN和C-MAX水平有望代表接受CAPD的患者的稳态水平。可以将这些水平与50％抑制性lamivudine进行比较，并且可能对提出剂量建议有用。结果：迄今为止，在罗利/达勒姆地区已经确定了五名患者，他们是这项研究的候选人。两名患者已经筛查和招募，其中一名已完成研究方案。预计该研究将在未来四个月内完成。意义：尽管这是一项小型研究，但它可能可以确定CAPD是否会显着影响消除拉米夫丁，并可以提供信息以提出剂量建议。