Center for Global Health Research, Haydom Lutheran Hospital, Haydom, Tanzania.
Division of Infectious Diseases and International Health, University of Virginia, Charlottesville.
J Pediatric Infect Dis Soc. 2020 Feb 28;9(1):14-20. doi: 10.1093/jpids/piy106.
Dosing recommendations for treating childhood tuberculosis (TB) were revised by the World Health Organization, yet so far, pharmacokinetic studies that have evaluated these changes are relatively limited. We evaluated plasma drug concentrations of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) among children undergoing TB treatment in Tanzania when these dosing recommendations were being implemented.
At the end of intensive-phase TB therapy, blood was obtained 2 hours after witnessed medication administration to estimate the peak drug concentration (C2h), measured using high-performance liquid chromatography or liquid chromatography-tandem mass spectrometry methods. Differences in median drug concentrations were compared on the basis of the weight-based dosing strategy using the Mann-Whitney U test. Risk factors for low drug concentrations were analyzed using multivariate regression analysis.
We enrolled 51 human immunodeficiency virus-negative children (median age, 5.3 years [range, 0.75-14 years]). The median C2hs were below the target range for each TB drug studied. Compared with children who received the "old" dosages, those who received the "revised" WHO dosages had a higher median C2h for RIF (P = .049) and PZA (P = .015) but not for INH (P = .624) or EMB (P = .143); however, these revised dosages did not result in the target range for RIF, INH, and EMB being achieved. A low starting dose was associated with a low C2h for RIF (P = .005) and PZA (P = .005). Malnutrition was associated with a low C2h for RIF (P = .001) and INH (P = .001).
Among this cohort of human immunodeficiency virus-negative Tanzanian children, use of the revised dosing strategy for treating childhood TB did not result in the target drug concentration for RIF, INH, or EMB being reached.
世界卫生组织修订了治疗儿童结核病（TB）的剂量建议，但迄今为止，评估这些变化的药代动力学研究相对有限。我们在坦桑尼亚实施这些剂量建议时，评估了正在接受 TB 治疗的儿童的利福平（RIF）、异烟肼（INH）、吡嗪酰胺（PZA）和乙胺丁醇（EMB）的血浆药物浓度。
在强化期 TB 治疗结束时，在观察到药物给药后 2 小时采集血液，以估计峰药物浓度（C2h），使用高效液相色谱法或液相色谱-串联质谱法进行测量。基于体重的给药策略，使用曼-惠特尼 U 检验比较中位数药物浓度的差异。使用多变量回归分析分析药物浓度低的危险因素。
我们纳入了 51 名人类免疫缺陷病毒阴性儿童（中位年龄为 5.3 岁[范围为 0.75-14 岁]）。研究的每种 TB 药物的 C2hs 均低于目标范围。与接受“旧”剂量的儿童相比，接受“修订后”世卫组织剂量的儿童的 RIF（P =.049）和 PZA（P =.015）的 C2h 中位数较高，但 INH（P =.624）或 EMB（P =.143）的 C2h 中位数没有较高；然而，这些修订后的剂量并没有使 RIF、INH 和 EMB 的目标范围达到。起始剂量低与 RIF（P =.005）和 PZA（P =.005）的 C2h 低有关。营养不良与 RIF（P =.001）和 INH（P =.001）的 C2h 低有关。
在这组人类免疫缺陷病毒阴性的坦桑尼亚儿童中，使用治疗儿童 TB 的修订剂量策略并未使 RIF、INH 或 EMB 的目标药物浓度达到。
