NOVEL METHODOLOGIES AND IVIVC APPROACHES TO ASSESS BIOEQUIVALENCE OF TOPICAL DRUG

仿制药现在是美国药品市场的主要组成部分。他们是一个 对消费者来说，品牌产品的替代产品具有吸引力，因为它们具有生物等效性和 因此，在质量、安全性和有效性方面是相同的，但在相当大的程度上可以获得 降低了成本。然而，仍然有一些产品没有或很少有通用替代品 可用。仿制药开发的一大障碍是赞助商必须证明 他们的产品与参考清单药物(RLD)具有生物等效性。这是一种特殊的 对皮肤病药物开发的挑战，因为这些药物在当地起作用， 而大多数生物等效性测试(BE)使用血液测量。因此，制造商 必须依赖于临床终点研究，这不仅昂贵且耗时，而且 也相当不可靠。因此，迫切需要新的、更有效的方法来 证明是局部用药。特别是，与In有很好相关性的体外方法 体内情况将极大地促进局部仿制药的发展。 我们将研究体外和体内的方法，以显示局部产品和将 在真皮药代动力学水平上建立体外-体内相关性(IVIVC)。 首先，我们将进行一项临床研究，以评估皮肤中的Be和非Be使用真皮开放 根据GCP和GLP进行血流微灌注(Dofm)。这个结果将是一枚“金子” 在真皮中的活体情况，并作为验证所有存在的参考 以及未来的体外方法，以了解他们预测体内情况的能力。 其次，我们将研究建立BE的体外方法，从唯一的FDA开始- 根据《FDA关于阿昔洛韦的指南草案》接受体外试验。到时候我们会的 研究基于DOFM的体外创新系统，作为BE的一种新的体外方法。 我们将使用Zovirax 5%的软膏(RLD)来演示BE和Zovirax 5%的乳膏 证明不是针对Zovirax 5%软膏的。相同的配方将被用于 在所有体外和体内系统中展示Be和Non-Be。所有的实验都将是 按照质量控制标准(ISO 9001、GCP、GLP)执行。EN ISO 13485)。一 将建立适用于所有项目样品的分析型高效液相-质谱仪/质谱仪 在GLP认证的实验室中根据ICH指南进行验证。BE和的所有结果 使用不同方法的非BE对将被分析其预测能力。通过交叉- 参考这些结果，我们计划将体外和体内的数据联系起来，以建立IVIVC。

Generic drugs now represent the major part of the US pharmaceutical market. They are an attractive alternative to brand products for consumers because they are bioequivalent and therefore the same in terms of quality, safety and efficacy, but available at a considerably reduced cost. However, there are still products for which no or few generic alternatives are available. A big barrier to generic drug development is that the sponsor must demonstrate that their product is bioequivalent to the reference-listed drug (RLD). This is a particular challenge for the development of dermatological drugs because these drugs act locally, whereas most tests for bioequivalence (BE) use blood measurements. Thus, manufacturers must rely on clinical endpoint studies, which are not only expensive and time consuming, but also rather unreliable. Hence, there is an urgent need for new, more efficient ways to demonstrate BE of topical drugs. In particular, in vitro methods that correlate well with the in vivo situation would significantly facilitate the development of topical generic drugs. We will investigate in vitro and in vivo methods to show BE of topical products and will establish in vitro - in vivo correlations (IVIVC) at the level of pharmacokinetics in the dermis. First, we will conduct a clinical study to assess BE and non-BE in skin using dermal open flow microperfusion (dOFM) according to GCP and GLP. The results will serve as a "gold standard" for the in vivo situation in the dermis, and as a reference for validating all present and future in vitro methods for their ability to predict the in vivo situation. Secondly, we will examine in vitro methods to establish BE, starting with the only FDA- accepted in vitro approach as per the "FDA Draft Guidance on Acyclovir". We will then investigate innovative in vitro systems based on dOFM as a new in vitro approach for BE. We will use Zovirax 5% ointment (RLD) to demonstrate BE and Zovirax 5% creme to demonstrate non-BE against Zovirax 5% ointment. The same formulations will be used to demonstrate BE and non-BE in all in vitro and in vivo systems. All experiments will be performed under quality-controlled standards (ISO 9001, GCP, GLP. EN ISO 13485). One analytical HPLC-MS/MS method suitable for all project samples will be developed and validated according to ICH guidelines in a GLP-certified laboratory. All results of the BE and non-BE pairs using different methods will be analyzed for their predictive power. By cross- referencing the results, we plan to correlate in vitro with in vivo data to establish IVIVC.