Charoo Naseem A, Cristofoletti Rodrigo, Dressman Jennifer B
Department of Research and Development, AlFalah Life Sciences Pvt Ltd, Budgam, India.
Emirates Pharma, Dubai, United Arab Emirates.
J Pharm Pharmacol. 2015 Aug;67(8):1156-69. doi: 10.1111/jphp.12411. Epub 2015 Apr 1.
The paediatric population undergoes developmental changes in gastric pH, gastric emptying, intestinal transit time, membrane permeability, protein binding, body water, distribution and metabolism. It is widely recognised that changes in these parameters may result in an alteration of the plasma profile and thus in key bioequivalence parameters such as Cmax (maximum plasma concentration of drug) and area under the plasma concentration vs time profile curve. The aim of this work is to assess the risk of extending the biowaiver for immediate release dosage formulations of fluconazole from the adult to the paediatric population.
Fluconazole exhibits good solubility and very rapid dissolution characteristics in various pH media. The absorption of fluconazole in children is known to be complete (over 90%) and not impaired by elevated pH, which is prevalent during the early days of life. Dose numbers calculated using body surface area are less than 1. Therefore, the risk to drug absorption due to differences in gastric pH, gastric emptying, intestinal transit, membrane permeability and metabolising enzymes between adults and children is considered low.
Thus, it can be safely concluded that fluconazole meets highly soluble and highly permeable criteria in the paediatric population and can be allocated to class 1 of the Biopharmaceutics Classification System (BCS) for this population as well as in adults. Additionally, fluconazole has an excellent safety profile in children, similar to that in adults. The BCS-based biowaiver claimed in adults can be safely extended to the paediatric population provided that the requirements in excipient selection and dissolution profile comparison using BCS-based dissolution conditions as stated in the biowaiver monograph for fluconazole immediate release dosage forms in adults are fulfilled.
儿科人群在胃pH值、胃排空、肠道转运时间、膜通透性、蛋白结合、身体水分、分布和代谢方面会经历发育变化。人们普遍认识到，这些参数的变化可能导致血浆特征的改变，进而导致关键生物等效性参数如Cmax（药物的最大血浆浓度）和血浆浓度-时间曲线下面积的改变。这项工作的目的是评估将氟康唑速释剂型从成人扩展到儿科人群的生物豁免风险。
氟康唑在各种pH介质中表现出良好的溶解性和非常快速的溶解特性。已知儿童对氟康唑的吸收是完全的（超过90%），且不受生命早期普遍存在的pH升高的影响。使用体表面积计算的剂量数小于1。因此，成人和儿童之间胃pH值、胃排空、肠道转运、膜通透性和代谢酶差异对药物吸收的风险被认为较低。
因此，可以安全地得出结论，氟康唑在儿科人群中符合高溶解性和高渗透性标准，并且在该人群以及成人中都可以归类为生物药剂学分类系统（BCS）的1类。此外，氟康唑在儿童中的安全性与成人相似。只要满足成人氟康唑速释剂型生物豁免专论中所述的辅料选择和使用基于BCS的溶出条件进行溶出曲线比较的要求，基于BCS的成人生物豁免就可以安全地扩展到儿科人群。
