Noguera-Julian Antoni, Wilhelmi Emma, Cussó Maria, Aarnoutse Rob, Colbers Angela, Martorell Loreto, López-Ramos Maria Goretti, Vinent Joan, Farré Rosa, Soy Dolors, Simó-Nebot Sílvia, Fortuny Clàudia
Malalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Servei d'Infectologia, Institut de Recerca Pediàtrica Sant Joan de Déu, 08950 Barcelona, Spain.
Departament de Cirurgia i Especialitats Medicoquirúrgiques, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain.
Antibiotics (Basel). 2025 Jan 12;14(1):74. doi: 10.3390/antibiotics14010074.
: Isoniazid (INH) remains a first-line drug for the treatment of tuberculosis (TB) in young children. In 2010, the WHO recommended an increase in the daily dose of INH up to 10 (7-15) mg/kg. Currently, there are no INH suspensions available in Europe. : We aimed to characterize the pharmacokinetics of a licensed INH suspension (10 mg/mL, Pharmascience Inc., Montreal, QC, Canada) in children receiving INH daily at 10 mg/kg in a single-center, open-label, non-randomized, phase IIa clinical trial (EudraCT Number: 2016-002000-31) in Barcelona (Spain). Samples were analyzed using a validated UPLC-UV assay. The -acetyltransferase 2 gene was examined to determine the acetylation status. A non-compartmental pharmacokinetic analysis was conducted. : Twenty-four patients (12 females) were included (primary chemoprophylaxis, = 12; TB treatment, = 9; and TB infection preventive treatment, = 3). The acetylator statuses were homozygous fast ( = 3), heterozygous intermediate ( = 18), and homozygous slow ( = 2; unavailable in one patient). The INH median (IQR) C and AUC values were 6.1 (4.5-8.2) mg/L and 23.0 (11.2-35.4) h∙mg/L; adult targets (>3 mg/L and 11.6-26.3 h∙mg/L) were not achieved in three and six cases, respectively. Gender, age at assessment (<2 or >2 years), and INH monotherapy (vs. combined TB treatment) had no impact on pharmacokinetic parameters. Significant differences in C ( = 0.030) and AUC ( = 0.011) values were observed based on acetylator status. Treatment was well tolerated, and no severe adverse events were observed; three patients developed asymptomatic mildly elevated alanine aminotransferase levels. : In infants and children receiving a daily INH suspension at 10 mg/kg, no safety concerns were raised, and the target adult levels were reached in the majority of patients.
异烟肼（INH）仍然是治疗幼儿结核病（TB）的一线药物。2010年，世界卫生组织建议将INH的每日剂量增加至10（7 - 15）mg/kg。目前，欧洲没有INH混悬液。我们旨在通过一项在西班牙巴塞罗那进行的单中心、开放标签、非随机的IIa期临床试验（欧盟临床试验编号：2016 - 002000 - 31），对一种已获许可的INH混悬液（10 mg/mL，加拿大魁北克省蒙特利尔市的法玛西亚公司）在每日接受10 mg/kg INH治疗的儿童中的药代动力学特征进行研究。使用经过验证的超高效液相色谱 - 紫外检测法对样本进行分析。检测 - 乙酰转移酶2基因以确定乙酰化状态。进行了非房室药代动力学分析。纳入了24例患者（12名女性）（初级化学预防，n = 12；结核病治疗，n = 9；以及结核感染预防性治疗，n = 3）。乙酰化状态为纯合快速型（n = 3）、杂合中间型（n = 18）和纯合缓慢型（n = 2；1例患者数据不可用）。INH的中位（四分位间距）Cmax和AUC值分别为6.1（4.5 - 8.2）mg/L和23.0（11.2 - 35.4）h∙mg/L；在3例和6例患者中分别未达到成人目标值（>3 mg/L和11.6 - 26.3 h∙mg/L）。性别、评估时的年龄（<2岁或>2岁）以及INH单药治疗（与联合结核病治疗相比）对药代动力学参数没有影响。基于乙酰化状态观察到Cmax（P = 0.030）和AUC（P = 0.011）值存在显著差异。治疗耐受性良好，未观察到严重不良事件；3例患者出现无症状的轻度丙氨酸氨基转移酶水平升高。对于每日接受10 mg/kg INH混悬液治疗的婴幼儿和儿童，未引发安全担忧，大多数患者达到了成人目标水平。
