Objectives . To determine the pharmacokinetic properties, tolerance, safety, and preliminary activity of stavudine in human immunodeficiency virus (HIV)-infected children.Design . Phase I/II, open and dose-ranging (0.125 to 4 mg/kg/day in two divided doses).Patients . Thirty-seven HIV-infected children (median age, 5.5 years; range, 7 months to 15 years) with a median CD4+ lymphocyte count at baseline of 242 cells/μL (range 2 to 2290 cells/μL). Thirty children had symptomatic HIV disease at entry; seven had HIV-related immunosuppression alone. Twenty-nine subjects had a history of prior zidovudine (ZDV) therapy.Results . As compared with adults receiving the same weight-adjusted doses, the children we studied had lower maximum observed stavudine plasma concentrations (CMAX) and area under the plasma concentration versus time curves (AUC), and more rapid stavudine elimination. The absolute oral bioavailability of the drug ranged from 61% to 78%. There was no plasma accumulation of the drug between day 1 and week 12. Week 12 cerebrospinal fluid stavudine concentrations in seven subjects, obtained approximately 2 to 3 hours after oral doses, ranged from 16% to 97% of concomitant plasma concentrations.Stavudine was well-tolerated and there were no dose-related clinical or laboratory adverse events. One subject with baseline neurologic abnormalities experienced a transient episode of apparent pain or discomfort in her fingers, possibly related to stavudine. All other adverse events were attributed to underlying disease. Stavudine activity, measured indirectly by CD4+ lymphocyte count and serum p24 antigen concentration changes, was observed in some subjects. Progression of HIV disease and survival correlated with prior ZDV therapy, HIV disease classification, baseline CD4+ lymphocyte count, and weight growth velocity.Conclusions . Stavudine appears to hold promise for the treatment of HIV infection in children. Its pharmacokinetic properties are consistent and predictable, and it appears to be remarkably well-tolerated and safe. Although our study was not designed to assess the drug's efficacy, preliminary clinical and laboratory evidence of activity was observed.
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机译：目标。为了确定司他夫定在人类免疫缺陷病毒（HIV）感染儿童中的药代动力学特性，耐受性，安全性和初步活性，设计。 I / II期，开放和剂量范围（分两次服用0.125至4 mg / kg /天）。三十七名艾滋病毒感染儿童（中位年龄为5.5岁;范围为7个月至15岁），基线时CD4 +淋巴细胞中位数为242个细胞/微升（2至2290个细胞/微升）。入院时有30名儿童出现症状性HIV疾病;七个单独进行了与HIV相关的免疫抑制。 29名受试者曾接受齐多夫定（ZDV）治疗史。与接受相同体重调整剂量的成年人相比，我们研究的儿童具有更低的最大观察到的司他夫定血浆浓度（CMAX）和血浆浓度-时间曲线下的面积（AUC），并且司他夫定消除更快。该药物的绝对口服生物利用度为61％至78％。在第1天至第12周之间没有血浆药物蓄积。口服剂量约2至3小时后，在7位受试者的第12周脑脊液司他夫定浓度为伴随血浆浓度的16％至97％。司他夫定很好耐受，没有剂量相关的临床或实验室不良事件。基线神经系统异常的一名受试者的手指出现短暂的明显疼痛或不适感，可能与司他夫定有关。所有其他不良事件均归因于潜在疾病。在某些受试者中观察到司他夫定活性，其通过CD4 +淋巴细胞计数和血清p24抗原浓度变化间接测量。 HIV疾病和生存的进展与先前的ZDV治疗，HIV疾病分类，基线CD4 +淋巴细胞计数和体重增长速度有关。 Stavudine似乎有望用于治疗儿童的HIV感染。它的药代动力学特性是一致且可预测的，并且似乎具有良好的耐受性和安全性。尽管我们的研究并非旨在评估这种药物的疗效，但仍观察到了有关活性的初步临床和实验室证据。
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