Stretcher B N, Pesce A J, Frame P T, Greenberg K A, Stein D S
University of Cincinnati College of Medicine, Ohio.
AIDS. 1994 Jun;8(6):763-9. doi: 10.1097/00002030-199406000-00007.
To determine the relationships between in vivo zidovudine (ZDV) phosphorylation in cells from HIV-infected patients and markers associated with disease progression and drug toxicity.
A pharmacokinetic study of ZDV metabolism sponsored by the AIDS Clinical Trials Group (protocol 161). Plasma and intracellular pharmacokinetics following a 100 mg oral dose of ZDV were determined at weeks 4 and 24 of initial therapy in adult patients. Plasma concentrations and phosphorylated ZDV were determined by radioimmunoassay, and area under the concentration-time curves (AUC) were compared with clinical data collected during the pharmacokinetic study.
An outpatient setting at the University of Cincinnati AIDS Treatment Center, Cincinnati, Ohio, USA.
HIV-infected adults with CD4+ lymphocyte counts 200-500 x 10(6) cells/l with no prior history of anti-HIV therapy and no active infections requiring systemic therapy. Of 30 patients enrolled, 21 were evaluable.
None.
AUC of plasma ZDV and intracellular total phosphorylated ZDV were compared with change from baseline of the following surrogate markers: CD4+ lymphocyte count, %CD4+ lymphocytes, CD4+/CD8+ cell ratio, serum beta 2-microglobulin, serum neopterin, neutrophils, red cell count, and hemoglobin.
No correlations between plasma AUC and markers of therapeutic response were observed. However, significant positive correlations were observed between the AUC of total phosphorylated ZDV and changes in the %CD4+ lymphocytes and CD4+/CD8+ lymphocyte ratio; a negative correlation was observed with change in hemoglobin. Patients who responded to ZDV therapy, as measured by these variables, demonstrated significantly higher intracellular AUC (> 3 pmol x h/10(6) cells) than those who did not (approximately 2 pmol x h/10(6) cells).
The ability of HIV-infected patients to phosphorylate ZDV correlates with changes in markers associated with drug effect and toxicity. Potential individualization of therapy through monitoring of total phosphorylated ZDV in patients therefore warrants further exploration.
确定HIV感染患者细胞内齐多夫定（ZDV）磷酸化与疾病进展及药物毒性相关标志物之间的关系。
一项由艾滋病临床试验组发起的ZDV代谢的药代动力学研究（方案161）。在成年患者初始治疗的第4周和第24周，测定口服100 mg ZDV后的血浆和细胞内药代动力学。通过放射免疫分析法测定血浆浓度和磷酸化ZDV，并将浓度-时间曲线下面积（AUC）与药代动力学研究期间收集的临床数据进行比较。
美国俄亥俄州辛辛那提大学艾滋病治疗中心的门诊。
CD4 +淋巴细胞计数为200 - 500×10⁶细胞/升的HIV感染成人，既往无抗HIV治疗史且无需要全身治疗的活动性感染。在30名入组患者中，21名可进行评估。
无。
将血浆ZDV的AUC和细胞内总磷酸化ZDV与以下替代标志物相对于基线的变化进行比较：CD4 +淋巴细胞计数、CD4 +淋巴细胞百分比、CD4 + / CD8 +细胞比值、血清β2 -微球蛋白、血清新蝶呤、中性粒细胞、红细胞计数和血红蛋白。
未观察到血浆AUC与治疗反应标志物之间的相关性。然而，观察到总磷酸化ZDV的AUC与CD4 +淋巴细胞百分比和CD4 + / CD8 +淋巴细胞比值的变化之间存在显著正相关；与血红蛋白的变化呈负相关。通过这些变量衡量，对ZDV治疗有反应的患者细胞内AUC（> 3 pmol·h/10⁶细胞）显著高于无反应者（约2 pmol·h/10⁶细胞）。
HIV感染患者磷酸化ZDV的能力与药物效应和毒性相关标志物的变化相关。因此，通过监测患者总磷酸化ZDV实现治疗个体化的可能性值得进一步探索。
