Family Infectious Diseases Clinical Research Unit, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
Antimicrob Agents Chemother. 2018 Oct 24;62(11). doi: 10.1128/AAC.00761-18. Print 2018 Nov.
Stavudine remains a useful replacement option for treatment for HIV children. WHO reduced the adult dose to 30 mg twice daily, which maintains efficacy and lowers mitochondrial toxicity. We explored intracellular stavudine triphosphate levels in children receiving a reduced dose of 0.5 to 0.75 mg/kg of body weight twice daily to investigate whether a similar dose optimization can safely be made. A population pharmacokinetic model was developed to describe the pharmacokinetics of intracellular stavudine triphosphate in 23 HIV children and 24 HIV adults who received stavudine at 0.5 mg/kg and 20 mg twice daily for 7 days, respectively. Simulations were employed to optimize the pediatric dosing regimen to match exposures in adults receiving the current WHO-recommended dose of 30 mg twice daily. A biphasic disposition model with first-order appearance and disappearance described the pharmacokinetics of stavudine triphosphate. The use of allometric scaling with fat-free mass characterized well the pharmacokinetics in both adults and children, and no other significant effect could be detected. Simulations of 30 mg twice daily in adults predicted median (interquartile range [IQR]) stavudine triphosphate minimum drug concentration () and maximum drug concentration () values of 13 (10 to 19) and 45 (38 to 53) fmol/10 cells, respectively. Targeting this exposure, simulations in HIV children were used to identify a suitable weight-band dosing approach (0.5 to 0.75 mg/kg), which was predicted to achieve median (IQR) and values of 13 (9 to 18) and 49 (40 to 58) fmol/10 cells, respectively. Weight-band dosing using a stavudine dose of 0.5 to 0.75 mg/kg is proposed, and it shows comparable exposures to adults receiving the current WHO-recommended dose of 30 mg twice daily. Our pharmacokinetic results suggest that the decreased stavudine dose in children >2 years would have a reduced toxic effect while retaining antiretroviral efficacy.
司他夫定仍然是治疗 HIV 儿童的一种有效替代选择。世界卫生组织将成人剂量降低至每日两次 30 毫克，这既能保持疗效，又能降低线粒体毒性。我们探索了接受每日两次 0.5 至 0.75mg/kg 体重的低剂量治疗的儿童体内司他夫定三磷酸的水平，以研究是否可以安全地进行类似的剂量优化。建立了一个群体药代动力学模型来描述 23 名接受 0.5mg/kg 体重剂量每日两次和 24 名接受 20mg 体重每日两次治疗 7 天的 HIV 儿童和成人的司他夫定三磷酸的体内药代动力学。通过模拟来优化儿科给药方案，以匹配接受世界卫生组织目前推荐的每日两次 30mg 剂量的成人的暴露量。司他夫定三磷酸的药代动力学呈两相处置模型，具有一级出现和消失。使用无脂肪质量的比例缩放很好地描述了成人和儿童的药代动力学，并且没有检测到其他显著影响。成人每日两次 30mg 的模拟预测司他夫定三磷酸最低药物浓度（）和最大药物浓度（）的中位数（四分位距 [IQR]）值分别为 13（10 至 19）和 45（38 至 53）fmol/10 细胞。针对这一暴露量，模拟 HIV 儿童的情况以确定合适的体重带剂量方法（0.5 至 0.75mg/kg），预计该方法将达到中位数（IQR）值分别为 13（9 至 18）和 49（40 至 58）fmol/10 细胞。建议使用 0.5 至 0.75mg/kg 的司他夫定剂量进行体重带剂量，这与接受世界卫生组织目前推荐的每日两次 30mg 剂量的成人的暴露量相当。我们的药代动力学结果表明，对于 2 岁以上的儿童，降低司他夫定剂量将减少毒性作用，同时保持抗逆转录病毒疗效。
