Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown 02129, MA, USA.
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring 20993, MD, USA.
J Control Release. 2024 Mar;367:864-876. doi: 10.1016/j.jconrel.2024.02.010. Epub 2024 Feb 19.
Generic drugs are essential for affordable medicine and improving accessibility to treatments. Bioequivalence (BE) is typically demonstrated by assessing a generic product's pharmacokinetics (PK) relative to a reference-listed drug (RLD). Accurately estimating cutaneous PK (cPK) at or near the site of action can be challenging for locally acting topical products. Certain cPK approaches are available for assessing local bioavailability (BA) in the skin. Stimulated Raman scattering (SRS) microscopy has unique capabilities enabling continuous, high spatial and temporal resolution and quantitative imaging of drugs within the skin. In this paper, we developed an approach based on SRS and a polymer-based standard reference for the evaluation of topical product BA and BE in human skin ex vivo. BE assessment of tazarotene-containing formulations was achieved using cPK parameters obtained within different skin microstructures. The establishment of BE between the RLD and an approved generic product was successfully demonstrated. Interestingly, within the constraints of the current study design the results suggest similar BA between the tested gel formulation and the reference cream formulation, despite the differences in the formulation/dosage form. Another formulation containing polyethylene glycol as the vehicle was demonstrated to be not bioequivalent to the RLD. Compared to using the SRS approach without a standard reference, the developed approach enabled more consistent and reproducible results, which is crucial in BE assessment. The abundant information from the developed approach can help to systematically identify key areas of study design that will enable a better comparison of topical products and support an assessment of BE.
仿制药对于平价药物和提高治疗可及性至关重要。生物等效性（BE）通常通过评估仿制药相对于参比上市药物（RLD）的药代动力学（PK）来证明。对于局部作用的局部用产品，准确估计作用部位的皮肤 PK（cPK）可能具有挑战性。某些 cPK 方法可用于评估皮肤中的局部生物利用度（BA）。受激拉曼散射（SRS）显微镜具有独特的功能，能够连续、高空间和时间分辨率以及对皮肤内药物进行定量成像。在本文中，我们开发了一种基于 SRS 和聚合物标准参考的方法，用于评估局部用产品在人体皮肤外植体中的 BA 和 BE。通过在不同的皮肤微结构中获得的 cPK 参数来评估他扎罗汀制剂的 BE。成功证明了 RLD 和已批准的仿制药之间的 BE 等效性。有趣的是，在当前研究设计的限制内，结果表明，尽管制剂/剂型不同，所测试的凝胶制剂与参考乳膏制剂之间的 BA 相似。另一种含有聚乙二醇作为载体的制剂被证明与 RLD 不具有生物等效性。与不使用标准参考的 SRS 方法相比，所开发的方法能够获得更一致和可重复的结果，这对于 BE 评估至关重要。所开发方法提供的丰富信息有助于系统地确定研究设计的关键领域，从而能够更好地比较局部用产品并支持 BE 评估。
