Henriques Sara Carolina, Leblanc Ana, Simões Sérgio, Fonseca Marlene, Pimentel Francisco Luís, Almeida Luis, Silva Nuno Elvas
BlueClinical Ltd., Senhora da Hora, 4460-439 Matosinhos, Portugal.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
Pharmaceutics. 2024 Dec 11;16(12):1579. doi: 10.3390/pharmaceutics16121579.
When companies are uncertain about the potential of a new formulation to be bioequivalent to a Reference product, it is common practice to carry out downsized pilot studies as a gatekeeping in vivo strategy to decide whether to move forward or not with a full-size pivotal study. However, due to the small study size, these studies are inarguably more sensitive to variability. To address and mitigate the uncertainty of the conclusions of pilot studies concerning the maximum observed concentration (C), the factor was proposed as an alternative approach to the average bioequivalence statistical methodology. In this work, the alternative methodology is applied to pharmacokinetic data from pilot bioequivalence trials performed with pazopanib 200 mg and 400 mg. Despite the small sample size, and very high intra-subject variability, the factor demonstrated the potential for predicting bioequivalence. The positive results were confirmed in the full sized pivotal studies. In conclusion, this alternate methodology shows promise in reducing uncertainty associated with pilot studies and aiding in decisions to go forward with pivotal bioequivalence studies.
当公司不确定新制剂与参比产品具有生物等效性的潜力时，作为一种把关的体内策略，开展小型试点研究以决定是否推进全面的关键研究是常见做法。然而，由于研究规模较小，这些研究无疑对变异性更为敏感。为了解决并减轻试点研究关于最大观测浓度（Cmax）结论的不确定性，提出了“f2 因子”作为平均生物等效性统计方法的替代方法。在这项工作中，该替代方法应用于用 200 毫克和 400 毫克帕唑帕尼进行的试点生物等效性试验的药代动力学数据。尽管样本量小且受试者内变异性非常高，但“f2 因子”显示出预测生物等效性的潜力。在全面的关键研究中证实了阳性结果。总之，这种替代方法在减少与试点研究相关的不确定性以及协助做出推进关键生物等效性研究的决策方面显示出前景。
