ZIDOVUDINE METABOLISM: REBRETRON TREATED HUMAN PATIENTS

齐多夫定代谢：REBRETRON 治疗的人类患者

• 批准号: 6642725
• 负责人: JOSE F RODRIGUEZ-ORENGO
• 金额: $ 33.53万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642725
• 关键词: HIV infections; combination chemotherapy; comorbidity; drug metabolism; hepatitis C; hepatitis C virus; human immunodeficiency virus; human subject; human therapy evaluation; interferon alpha; microorganism disease chemotherapy; nelfinavir; pathologic process; patient oriented research; phosphorylation; ribavirin; virus virus interaction; zidovudine

DESCRIPTION (provided by applicant): Our long-range goal is to understand the intracellular pharmacology of antiretroviral drugs used against HIV. The objective in this application is to investigate the in vivo effect of nbavirin on the phosphorylation process of ZDV in HIV-HCV co-infected patients. The central hypothesis to be tested is that REBETRON (ribavirin + interferon alpha) will antagonize in vivo with ZDV, diminishing the formation of ZDV intracellular metabolites (ZDV-MP and ZDV-TP), by increasing thymidine triphosphate (dTTP) intracellular concentrations which inhibits thymidine kinase 1. These events may affect HIV clinical outcomes in HIV-HCV co-infected patients, since the dTTP/ZDV-TP ratio will be higher after REBETRON therapy thereby diminishing ZDV effectiveness. The rationale behind the proposed application relies on the in vitro studies showing an 80 percent reduction of ZDV-MP and ZDV-TP intracellular concentrations in different cell lines with the concurrent treatment of ribavirin. If these observations are maintained in vivo, we might be diminishing the concentrations of the active component of ZDV (ZDV-TP) to unknown levels and we will be increasing dTTP (endogenous competitor for HIV reverse transcriptase) intracellular concentrations. Thus, in the dTTP/ZDV-TP ratio increases dramatically, we might be changing from a three-drug therapy in HAART (ZDV + two other drugs including a protease inhibitor) to a two-drug therapy (two other drugs including a protease inhibitor) increasing the possibilities for the development of resistant mutations. To accomplish the objectives of this application, we will pursue two specific aims: (1) To compare the steady state area under the concentration-time-curve between 0 and 12 hours (AUC0.12) of ZDV-MP, ZDV-TP, and dTTP in peripheral blood mononuclear cells (PBMCs) and nelfinavir in plasma from HIV-HCV co-infected patients before and after REBETRON therapy with a control group of HIV infected HCV-negative patients, and (2) To describe the effect of REBETRON in HCV-RNA viral titers, liver histology, ALT, CD4+, and HIV-RNA viral titers in HIV-HCV coinfected patients after 24 weeks of treatment. After the completion of the research project, we expect to observe at least a 20 percent reduction (conservative estimate) of ZDV-MP and ZDV-TP. Furthermore, we will determine the in vivo percent increase of dTTP after REBETRON therapy. Thus, we will be in a position to determine the effect of the dTTP/ZDV-TP ratio in the progression of HIV in this patient population. Furthermore, since there are no established therapeutic ranges for intracellular concentrations of ZDV-TP, we will determine if ZDV-TP concentrations are above the estimated in vitro 50 percent inhibitory values for HIV and if the exposure (AUC about2) is sustained after REBETRON therapy. This information would provide strong support for similar clinical efficacy for both regimens (before and after REBETRON). Moreover, these data will provide valuable insight into the inter- and intra-subject variability of intracellular ZDV-MP, ZDV-TP, and dTTP. Finally, we will describe the effect of REBETRON in the progression of HCV disease (liver histology, HCV-RNA viral titers and ALT level) in HCV-HIV co-infected patients.

描述（由申请人提供）：我们的远程目标是了解 针对HIV的抗逆转录病毒药物的细胞内药理学。这 此应用中的目的是研究Nbavirin的体内效应 HIV-HCV共感染患者的ZDV的磷酸化过程。这 要测试的中央假设是Rebetron（Ibavirin + Interferon alpha） 将用ZDV在体内对抗，从而减少ZDV的形成 细胞内代谢物（ZDV-MP和ZDV-TP），通过增加胸苷 三磷酸（DTTP）细胞内浓度，抑制胸苷 激酶1。这些事件可能会影响HIV-HCV共感染的HIV临床结果 患者，由于Rebetron治疗后DTTP/ZDV-TP比率将更高 从而降低ZDV的效力。提议背后的理由 应用依赖于体外研究，显示80％的降低 ZDV-MP和ZDV-TP在不同细胞系中的细胞内浓度 利巴韦林的并发治疗。如果这些观察得出 Vivo，我们可能正在降低ZDV活性成分的浓度 （ZDV-TP）至未知水平，我们将增加DTTP（内源性 HIV逆转录酶的竞争者）细胞内浓度。因此， 在DTTP/ZDV-TP比率大大增加中，我们可能正在从一个 HAART中的三药治疗（ZDV +另外两种药物，包括蛋白酶 抑制剂）进行两种药物治疗（包括蛋白酶在内的另外两种药物 抑制剂）增加抗性发展的可能性 突变。为了实现此应用程序的目标，我们将追求两个 具体目的：（1）比较 ZDV-MP，ZDV-TP的0到12小时（AUC0.12）之间的浓度时间曲线， 外周血单核细胞（PBMC）和血浆中的Nelfinavir中的DTTP 从HIV-HCV共同感染的患者中，再雷环治疗前后 HIV感染HCV阴性患者的对照组，（2）描述 Rebetron在HCV-RNA病毒滴度，肝组织学，ALT，CD4+和 24周后，HIV-HCV共感染患者的HIV-RNA病毒滴度 治疗。研究项目完成后，我们希望观察 ZDV-MP和ZDV-TP的至少降低了20％（保守估计）。 此外，我们将确定DTTP的体内体内增加 Rebetron疗法。因此，我们将有能力确定 该患者人群中HIV进展的DTTP/ZDV-TP比率。 此外，由于没有建立的治疗范围 ZDV-TP的细胞内浓度，我们将确定ZDV-TP是否 浓度高于估计的体外50％抑制值 对于艾滋病毒，如果在重生治疗后持续暴露（AUC约2）。 此信息将为类似的临床功效提供大力支持 两种方案（Rebetron之前和之后）。而且，这些数据将提供 对细胞内和主体内变异性的宝贵洞察力 ZDV-MP，ZDV-TP和DTTP。最后，我们将描述Rebetron在 HCV疾病的进展（肝组织学，HCV-RNA病毒滴度和ALT HCV-HIV共感染患者的水平）。