Desmond Tutu TB Center, Department of Pediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch Universitygrid.11956.3a, Cape Town, South Africa.
Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa.
Antimicrob Agents Chemother. 2022 Jun 21;66(6):e0226421. doi: 10.1128/aac.02264-21. Epub 2022 May 4.
Treatment options for children with Rifampicin-resistant tuberculosis (RR-TB) remain limited, and para-aminosalicylic acid (PAS) is still a relevant component of treatment regimens. Prevention of resistance to companion drugs by PAS is dose related, and at higher concentrations, PAS may exhibit significant bactericidal activity in addition to its bacteriostatic properties. The optimal dosing of PAS in children is uncertain, specifically for delayed-release granule preparations, which are the most used. A population pharmacokinetic model was developed describing PAS pharmacokinetics in children receiving routine RR-TB treatment. Model-based simulations evaluated current World Health Organization (WHO) weight-band doses against the adult pharmacokinetic target of 50 to 100 mg/liter for peak concentrations. Of 27 children included, the median (range) age and weight were 3.87 (0.58 to 13.7) years and 13.3 (7.15 to 30.5) kg, respectively; 4 (14.8%) were HIV positive. PAS followed one-compartment kinetics with first-order elimination and transit compartment absorption. The typical clearance in a 13-kg child was 9.79 liters/h. Increased PAS clearance was observed in both pharmacokinetic profiles from the only patient receiving efavirenz. No effect of renal function, sex, ethnicity, nutritional status, HIV status, antiretrovirals (lamivudine, abacavir, and lopinavir-ritonavir), or RR-TB drugs was detected. In simulations, target concentrations were achieved only using the higher WHO dose range of 300 mg/kg once daily. A transit compartment adequately describes absorption for the slow-release PAS formulation. Children should be dosed at the higher range of current WHO-recommended PAS doses and in a once-daily dose to optimize treatment.
利福平耐药结核病（RR-TB）患儿的治疗选择仍然有限，对氨基水杨酸（PAS）仍然是治疗方案的重要组成部分。PAS 对伴随药物耐药性的预防与剂量有关，在较高浓度下，PAS 除了具有抑菌作用外，还可能具有显著的杀菌活性。PAS 在儿童中的最佳剂量不确定，特别是对于最常用的缓释颗粒制剂。开发了一种群体药代动力学模型，用于描述接受常规 RR-TB 治疗的儿童中 PAS 的药代动力学。基于模型的模拟评估了目前世界卫生组织（WHO）按体重划分的剂量与成人药代动力学目标（峰浓度 50-100mg/L）相比的情况。在 27 名纳入的儿童中，中位数（范围）年龄和体重分别为 3.87（0.58-13.7）岁和 13.3（7.15-30.5）kg；4 名（14.8%）HIV 阳性。PAS 遵循一室模型动力学，具有一级消除和转运室吸收。13kg 儿童的典型清除率为 9.79 升/小时。仅在接受依非韦伦的唯一患者的药代动力学谱中观察到 PAS 清除率增加。未检测到肾功能、性别、种族、营养状况、HIV 状态、抗逆转录病毒药物（拉米夫定、阿巴卡韦和洛匹那韦-利托那韦）或 RR-TB 药物的影响。在模拟中，仅使用当前 WHO 推荐的 PAS 剂量的较高范围（每日 300mg/kg，一次）才能达到目标浓度。转运室可充分描述缓释 PAS 制剂的吸收情况。为了优化治疗，儿童应按当前 WHO 推荐的 PAS 剂量较高范围和每日一次剂量给药。
