School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region.
Europharm Laboratoires Co. Ltd., 12-14 Dai Wang Street, Tai Po Industrial Estate, Tai Po, New Territories, Hong Kong Special Administrative Region.
J Control Release. 2022 Jun;346:275-288. doi: 10.1016/j.jconrel.2022.04.024. Epub 2022 Apr 28.
Although in-vivo bioequivalence (BE) study serves as a golden standard for establishing interchangeability of oral dosage forms, it remains challenging for products with high inter-subject variability such as mesalazine enteric-coated tablet to fulfil the BE criteria set by regulatory authorities. Mesalazine, as a BCS class IV drug, targets to be delivered to distal ileum or colon with a pH-sensitive polymer coating for the remission of ulcerative colitis. Through population pharmacokinetic (PK) analysis and in-vitro in-vivo correlation (IVIVC) modeling on the dissolution and BE data of a generic enteric-coated product (EM) and its reference Salofalk® 250 mg tablet (SM), we for the first time revealed the underlying mechanism of the high inter-subject variability for such delayed-release formulation. It was also noted that the in-vivo start time of absorption (T) for EM and SM was positively correlated with their in-vitro lag time (T) under the USP three-stage dissolution condition and reversely correlated with their in-vivo bioavailability. The varied oral bioavailability of mesalazine enteric-coated tablet was mainly due to the varied N-acetyltransferase activities along GI tract. Although such extensive intestinal first-pass metabolism with large individual differences led to a significant variation of mesalazine C (coefficient of variation: 60-63.5%) and AUC (coefficient of variation: 37.5-46.9%), the corresponding variations in the total absorbed mesalazine (mesalazine and its metabolite N-acetyl mesalazine) were significantly reduced by 12 to 45%. Since the BE purpose for mesalazine enteric-coated tablet focused on their comparable safety profiles, total absorbed mesalazine was recommended to be adopted for the development of the IVIVC model and BE evaluation for EM. All in all, our model-based approach has not only successfully identified the key factors that affect the BE of EM to guide its further formulation optimization, but also demonstrated the indispensable role of modeling in the development of generic pharmaceutical product at its early stages.
尽管体内生物等效性（BE）研究是确定口服剂型可互换性的金标准，但对于像美沙拉嗪肠溶片这样个体间变异性较高的产品，要满足监管机构设定的 BE 标准仍然具有挑战性。美沙拉嗪属于 BCS 分类 IV 类药物，其目标是通过 pH 敏感聚合物包衣递送到回肠末端或结肠，以缓解溃疡性结肠炎。通过对一种仿制药（EM）及其参比制剂 Salofalk® 250mg 肠溶片（SM）的溶出度和 BE 数据进行群体药代动力学（PK）分析和体内外相关性（IVIVC）建模，我们首次揭示了这种缓控释制剂个体间变异性高的潜在机制。此外，还发现 EM 和 SM 的体内吸收起始时间（T）与它们在 USP 三阶段溶出条件下的体外滞后时间（T）呈正相关，与体内生物利用度呈负相关。美沙拉嗪肠溶片的口服生物利用度差异主要归因于胃肠道中 N-乙酰转移酶活性的差异。尽管这种广泛的肠道首过代谢和个体差异较大导致美沙拉嗪 C（变异系数：60-63.5%）和 AUC（变异系数：37.5-46.9%）的显著变化，但总吸收的美沙拉嗪（美沙拉嗪及其代谢物 N-乙酰美沙拉嗪）的变化则显著减少了 12-45%。由于美沙拉嗪肠溶片的 BE 目的侧重于其可比的安全性，因此建议采用总吸收美沙拉嗪来建立 IVIVC 模型和评估 EM 的 BE。总之，我们的基于模型的方法不仅成功确定了影响 EM 的 BE 的关键因素，以指导其进一步的制剂优化，还证明了建模在早期开发仿制药产品中的不可或缺作用。
