Wang Zilong, Yang Yujie, Cao Zhihai, Dallmann André, Hu Wei, Zhang Wei, Zhang Qian, Zheng Liang
School of Pharmacy, Anhui Medical University, Hefei 230601, China; Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
Department of Pharmacy, The Third People's Hospital of Chengdu, College of Medicine, Southwest Jiaotong University, Chengdu, China.
J Pharm Sci. 2025 Jul;114(7):103830. doi: 10.1016/j.xphs.2025.103830. Epub 2025 May 9.
Tapentadol, an effective opioid analgesic, is indicated for the treatment of pain that cannot be managed with non-opioid medications. This study employed a physiologically based pharmacokinetic (PBPK) model to characterize the disposition of tapentadol in children across different age groups and to refine pediatric dosing strategies. Initially, an adult PBPK model was developed using the 'middle-out' strategy, which was then adjusted by scaling anatomical and physiological parameters to apply it to pediatric populations. The model's precision was confirmed by comparing the simulated plasma concentrations in a virtual population with empirical data. Utilizing this model, we translated dosages from adults to children and assessed weight-adjusted dosages for children aged 2 to 18 years and those under 2 years. The ratios of predicted to observed pharmacokinetic (PK) parameters for adult tapentadol ranged from 0.80 to 1.40 with the pediatric population's predictive mean absolute prediction error (MAPE) being less than 0.45. Based on model validation, we have established the following fixed-dose regimen for tapentadol oral solution for children across various age groups: 2.5 mg for 0-1 month, 3.5 mg for 1-3 months, 5 mg for 3-6 months, 8.5 mg for 6 months to 1 year, 13 mg for 1-2 years, 20 mg for 2-6 years, 35 mg for 6-12 years, and 60 mg for 12-18 years. The results of this study may offer guidance for the clinical investigation of tapentadol in pediatric patients and for developing PBPK models for drugs undergoing multiple metabolic pathways.
曲马多是一种有效的阿片类镇痛药，适用于治疗非阿片类药物无法控制的疼痛。本研究采用基于生理的药代动力学（PBPK）模型来描述曲马多在不同年龄组儿童中的处置情况，并优化儿科给药策略。最初，使用“由中至外”策略开发了一个成人PBPK模型，然后通过缩放解剖学和生理学参数对其进行调整，以应用于儿科人群。通过将虚拟人群中的模拟血浆浓度与经验数据进行比较，证实了该模型的准确性。利用该模型，我们将成人剂量换算为儿童剂量，并评估了2至18岁以及2岁以下儿童的体重调整剂量。成人曲马多预测药代动力学（PK）参数与观察值的比值范围为0.80至1.40，儿科人群的预测平均绝对预测误差（MAPE）小于0.45。基于模型验证，我们为不同年龄组的儿童建立了以下曲马多口服溶液固定剂量方案：0至1个月为2.5毫克，1至3个月为3.5毫克，3至6个月为5毫克，6个月至1岁为8.5毫克，1至2岁为13毫克，2至6岁为20毫克，6至12岁为35毫克，12至18岁为60毫克。本研究结果可为曲马多在儿科患者中的临床研究以及为具有多种代谢途径的药物开发PBPK模型提供指导。
