PK Sciences, Novartis Institutes for Biomedical Research, Jinke Road 4218, Pudong District, Shanghai 201203, People's Republic of China.
Pharmacometrics, Novartis Pharma AG, Basel 4002, Switzerland.
J Pharm Sci. 2017 Nov;106(11):3402-3409. doi: 10.1016/j.xphs.2017.06.010. Epub 2017 Jun 17.
Tobramycin inhalation solution given as a twice daily inhalation of nebulized aerosols of 300 mg is approved for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis patients over 6 years of age. To investigate tobramycin pharmacokinetics (PK) after inhalation of tobramycin in pediatric cystic fibrosis patients below 7 years, a population PK approach was used to evaluate tobramycin PK data in patients 6 months to 44 years of age from 4 clinical studies. The final model used a 2-compartmental, first-order absorption model with effect of body mass index on the apparent central volume of distribution. Relative bioavailability in patients between 6 months and 7 years increased with age by a linear relationship, and was modeled as a ratio to that of patients over 7 years. Simulation showed that steady-state concentrations of tobramycin are lower in pediatric patients 6 months to 6 years than those in patients over 6 years. However, systemic exposure is not predictive of clinical efficacy due to direct dosing at the infection site. P aeruginosa eradication rate and safety profile in patients less than 7 years of age were similar to patients older than 6 years; therefore, no dose adjustment is warranted in the younger pediatric patients.
妥布霉素吸入溶液作为每日两次雾化吸入的气溶胶，每次 300mg，获批用于治疗 6 岁以上囊性纤维化患者的铜绿假单胞菌感染。为了研究妥布霉素在 7 岁以下儿科囊性纤维化患者中的药代动力学（PK），采用群体 PK 方法评估了来自 4 项临床研究的 6 个月至 44 岁患者的妥布霉素 PK 数据。最终模型采用二室、一级吸收模型，身体质量指数对表观中央分布容积有影响。6 个月至 7 岁患者的相对生物利用度随年龄呈线性增加，并且通过与 7 岁以上患者的比值进行建模。模拟表明，6 个月至 6 岁的儿科患者的妥布霉素稳态浓度低于 6 岁以上患者。然而，由于直接在感染部位给药，全身暴露并不能预测临床疗效。6 岁以下患者的铜绿假单胞菌清除率和安全性与 6 岁以上患者相似；因此，不建议在年龄较小的儿科患者中调整剂量。
