Pepin Xavier J H, Johansson Soares Medeiros Juliana, Deris Prado Livia, Suarez Sharp Sandra
Simulations Plus, Inc., 42505 10th Street West, Lancaster, CA 93534-7059, USA.
Technological Development Coordination, Instituto de Tecnologia em Fármacos (Farmanguinhos)/Fiocruz, Av. Cmte. Guaranys, 447-Jacarepaguá, Rio de Janeiro 22775-903, Brazil.
Pharmaceutics. 2024 Dec 12;16(12):1587. doi: 10.3390/pharmaceutics16121587.
The combination of isoniazid (INH) and rifampicin (RIF) is indicated for the treatment maintenance phase of tuberculosis (TB) in adults and children. In Brazil, there is no current reference listed drug for this indication in children. Farmanguinhos has undertaken the development of an age-appropriate dispersible tablet to be taken with water for all age groups from birth to adolescence. The primary objective of this work was to develop and validate a physiologically-based biopharmaceutics model (PBBM) in GastroPlus, to link the product's in vitro performance to the observed pharmacokinetic (PK) data in adults and children. : The PBBM was developed based on measured or predicted physico-chemical and biopharmaceutical properties of INH and RIF. The metabolic clearance was specified mechanistically in the gut and liver for both parent drugs and acetyl-isoniazid. The model incorporated formulation related measurements such as dosage form disintegration and dissolution as inputs and was validated using extensive literature as well as in house clinical data. : The model was used to predict the exposure in children across the targeted dosing regimen for each age group using the new age-appropriate formulation. Probabilistic models of efficacy and safety versus exposure, combined with real world data on children, were utilized to assess drug efficacy and safety in the target populations. : The model predictions (systemic exposure) along with clinical data from the literature linking systemic exposure to clinical outcomes confirmed that the proposed dispersible pediatric tablet and dosing regimen are anticipated to be as safe and as effective as adult formulations at similar doses.
异烟肼（INH）和利福平（RIF）联合用药适用于成人和儿童结核病（TB）治疗的维持阶段。在巴西，目前尚无该适应症用于儿童的参考上市药物。法尔芒吉尼奥药厂已着手研发一种适合各年龄段（从出生到青春期）的可分散片剂，用水冲服。这项工作的主要目标是在GastroPlus中开发并验证一种基于生理学的生物药剂学模型（PBBM），将该产品的体外性能与在成人和儿童中观察到的药代动力学（PK）数据联系起来。：PBBM是基于异烟肼和利福平已测得或预测的物理化学和生物药剂学性质开发的。对两种母体药物和乙酰异烟肼在肠道和肝脏中的代谢清除进行了机制性设定。该模型纳入了与制剂相关的测量值，如剂型崩解和溶出作为输入，并使用大量文献以及内部临床数据进行了验证。：该模型用于预测各年龄组使用新的适合年龄的制剂在目标给药方案下儿童的暴露量。利用疗效和安全性与暴露量的概率模型，结合儿童的实际数据，评估目标人群中的药物疗效和安全性。：模型预测（全身暴露量）以及文献中关于全身暴露量与临床结果关联的临床数据证实，拟议的儿科可分散片剂和给药方案预计在相似剂量下与成人制剂一样安全有效。
