Quantitative Pharmacology, Merck KGaA, Darmstadt, Germany.
University of Paris Descartes, Paris, France.
CPT Pharmacometrics Syst Pharmacol. 2019 Apr;8(4):220-229. doi: 10.1002/psp4.12385. Epub 2019 Feb 26.
Physiologically-based pharmacokinetic models are increasingly applied for pediatric dose selection along with traditional methods such as allometry and population pharmacokinetic models. We report a retrospective evaluation of the three methods. Pediatric population pharmacokinetic models sourced from literature for a subset of eight compounds were used to predict clearances for children < 2 years when they were within the modeled age range (interpolation, N = 11) or including those outside the modeled age range (interpolation and extrapolation, N = 18). Pediatric/adult clearance ratios were evaluated with a strict performance criterion of 0.8-1.25 and with twofold criteria. For children > 2 years, 58-75% of the clinical studies (N = 10) met the strict criteria, and > 80% of the clinical studies were predicted within twofold by all three methods. For children < 2 years, physiologically-based pharmacokinetic, allometry with age-dependent exponents, and pediatric population pharmacokinetic models predict 54%, 82%, and 64% within twofold of the observed, respectively.
生理药代动力学模型越来越多地应用于儿科剂量选择，同时还应用了传统方法，如比例法和群体药代动力学模型。我们报告了这三种方法的回顾性评估。从文献中获取了 8 种化合物的子集的儿科群体药代动力学模型，用于预测模型年龄范围内（插值，N=11）或包括模型年龄范围外的儿童（插值和外推，N=18）的清除率。使用严格的性能标准 0.8-1.25 和两倍标准评估儿科/成人清除率比值。对于>2 岁的儿童，58-75%的临床研究（N=10）符合严格标准，所有三种方法均预测>80%的临床研究在两倍范围内。对于<2 岁的儿童，生理药代动力学模型、年龄依赖性指数的比例法和儿科群体药代动力学模型分别预测观察值的 54%、82%和 64%在两倍范围内。
