Mangas-Sanjuán Víctor, Simón Marta, González-Rojano Esperanza, Ochoa Dolores, Abad-Santos Francisco, Román Manuel, Ramos Mercedes, Govantes Carlos, García-Arieta Alfredo
Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46100 Valencia, Spain.
Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia-University of Valencia, 46100 Valencia, Spain.
Pharmaceutics. 2023 Jan 26;15(2):409. doi: 10.3390/pharmaceutics15020409.
(1) Background: this article investigates which PK metrics in a single-dose study (concentration at the end of posology interval, C, partial areas under the curve, pAUCs, or half-value duration, HVD) are more sensitive and less variable for predicting the failure of a prolonged-release product at steady-state that was the bioequivalent for C, AUC and AUC, in the single-dose study; (2) Methods: a cross-over study was performed in 36 subjects receiving desvenlafaxine 100 mg prolonged-release tablets. Conventional (C, AUC and AUC) and additional (C, pAUCs and HVD) PK metrics were considered after single-dose conditions. Predicted PK metrics at steady state (AUC, C, and C) were derived using a population PK model approach; (3) Results: the existing differences in the shape of the concentration-time curves precluded to show equivalence for C in the simulated study at steady state. This failure to show equivalence at steady state was predicted by C, pAUCs and HVD in the single-dose study. C was the most sensitive metric for detecting the different shape, with a lower intra-subject variability than HVD; (4) Conclusions: conventional PK metrics for single-dose studies (C, AUC and AUC) are not enough to guarantee bioequivalence at steady state for prolonged-release products.
(1) 背景：本文研究单剂量研究中的哪些药代动力学指标（给药间隔结束时的浓度C、曲线下部分面积pAUCs或半值持续时间HVD）在预测长效产品在稳态时失效方面更敏感且变异性更小，该长效产品在单剂量研究中C、AUC和AUC生物等效；(2) 方法：对36名接受100mg去甲文拉法辛缓释片的受试者进行交叉研究。单剂量给药后考虑常规（C、AUC和AUC）和额外的（C、pAUCs和HVD）药代动力学指标。使用群体药代动力学模型方法推导稳态时的预测药代动力学指标（AUC、C和C）；(3) 结果：浓度-时间曲线形状的现有差异使得在模拟的稳态研究中无法显示C的等效性。单剂量研究中的C、pAUCs和HVD预测了稳态时无法显示等效性。C是检测不同形状最敏感的指标，其受试者内变异性低于HVD；(4) 结论：单剂量研究的常规药代动力学指标（C、AUC和AUC）不足以保证长效产品在稳态时的生物等效性。
