Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
CPT Pharmacometrics Syst Pharmacol. 2024 Aug;13(8):1394-1408. doi: 10.1002/psp4.13167. Epub 2024 Jun 4.
Pantoprazole is a proton pump inhibitor indicated for the treatment of gastroesophageal reflux disease, a condition that disproportionately affects children with obesity. Appropriately dosing pantoprazole in children with obesity requires understanding the body size metric that best guides dosing, but pharmacokinetic (PK) trials using traditional techniques are limited by the need for larger sample sizes and frequent blood sampling. Physiologically-based PK (PBPK) models are an attractive alternative that can account for physiologic-, genetic-, and drug-specific changes without the need for extensive clinical trial data. In this study, we explored the effect of obesity on pantoprazole PK and evaluated label-suggested dosing in this population. An adult PBPK model for pantoprazole was developed using data from the literature and accounting for genetic variation in CYP2C19. The adult PBPK model was scaled to children without obesity using age-associated changes in anatomical and physiological parameters. Lastly, the pediatric PBPK model was expanded to children with obesity. Three pantoprazole dosing strategies were evaluated: 1 mg/kg total body weight, 1.2 mg/kg lean body weight, and US Food and Drug Administration-recommended weight-tiered dosing. Simulated concentration-time profiles from our model were compared with data from a prospective cohort study (PAN01; NCT02186652). Weight-tiered dosing resulted in the most (>90%) children with pantoprazole exposures in the reference range, regardless of obesity status or CYP2C19 phenotype, confirming results from previously published population PK models. PBPK models may allow for the efficient study of physiologic and developmental effects of obesity on PK in special populations where clinical trial data may be limited.
泮托拉唑是一种质子泵抑制剂，用于治疗胃食管反流病，这种疾病在肥胖儿童中发病率较高。为肥胖儿童适当给药泮托拉唑需要了解最佳指导剂量的身体大小指标，但使用传统技术的药代动力学（PK）试验受到需要更大样本量和频繁采血的限制。基于生理学的 PK（PBPK）模型是一种有吸引力的替代方法，它可以在不需要大量临床试验数据的情况下，考虑生理、遗传和药物特异性变化。在这项研究中，我们探讨了肥胖对泮托拉唑 PK 的影响，并评估了该人群的标签建议剂量。使用文献中的数据并考虑 CYP2C19 的遗传变异，为泮托拉唑开发了成人 PBPK 模型。使用与年龄相关的解剖学和生理学参数变化，将成人 PBPK 模型扩展到无肥胖的儿童。最后，将儿科 PBPK 模型扩展到肥胖儿童。评估了三种泮托拉唑给药策略：1mg/kg 总体重、1.2mg/kg 去脂体重和美国食品和药物管理局推荐的体重分层剂量。我们模型的模拟浓度-时间曲线与前瞻性队列研究（PAN01；NCT02186652）的数据进行了比较。无论肥胖状况或 CYP2C19 表型如何，分层剂量都导致超过 90%的儿童泮托拉唑暴露在参考范围内，这证实了先前发表的群体 PK 模型的结果。PBPK 模型可用于研究肥胖对特殊人群 PK 的生理和发育影响，在这些人群中，临床试验数据可能有限。
