NOVEL METHODOLOGIES AND IVIVC APPROACHES TO ASSESS BIOEQUIVALENCE OF TOPICAL DRUG

评估外用药物生物等效性的新方法和 IVIVC 方法

• 批准号: 8904331
• 负责人: Frank Sinner
• 金额: $ 25万
• 依托单位: JOANNEUM RESEARCH FORSCHUNGSGESELLSCHAFT MBH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904331
• 关键词: NOVEL; METHODOLOGIES; IVIVC; APPROACHES; ASSESS

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will examine in vitro methods to establish BE, starting with the only FDA- accepted in vitro approach as per the "FDA Draft Guidance on Acyclovir".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.

仿制药现在是美国医药市场的主要部分。他们是一个 对消费者来说，品牌产品的替代品是有吸引力的，因为它们是生物等效的， 因此，在质量、安全性和有效性方面相同，但在相当大的程度上， 降低成本。然而，仍然有一些产品没有或很少有通用替代品， available.仿制药开发的一大障碍是， 他们的产品与参考上市药物（RLD）具有生物等效性。这是一个特别 皮肤科药物的开发面临挑战，因为这些药物在局部发挥作用， 而生物等效性（BE）的大多数测试使用血液测量。因此，制造商 必须依赖临床终点研究，这不仅昂贵且耗时， 也相当不可靠。因此，迫切需要新的、更有效的方法， 显示局部用药的BE。特别是，与体内代谢相关性良好的体外方法， 体内情况将显着促进局部仿制药的开发。 我们将研究体外和体内方法，以显示局部产品的BE，并将 在真皮中的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， 根据GCP和GLP进行微流灌注（dOFM）。结果将作为“黄金 真皮中的体内情况的“标准”，并作为验证所有存在的 以及未来的体外方法，因为它们能够预测体内情况。 其次，我们将研究建立BE的体外方法，从唯一的FDA- 根据“FDA阿昔洛韦指南草案”，接受体外方法。然后我们将 研究基于dOFM的创新体外系统作为BE的新体外方法。 我们将使用Zovirax 5%软膏（RLD）来证明BE和Zovirax 5%乳膏， 证明对Zovirax 5%软膏无BE。将使用相同的制剂 在所有体外和体内系统中证明BE和非BE。所有的实验都将 根据质量控制标准（ISO 9001、GCP、GLP）进行。EN ISO 13485）。一 将开发适用于所有项目样品的HPLC-MS/MS分析方法， 在GLP认证的实验室中根据ICH指导原则进行验证。所有BE和 将分析使用不同方法的非BE对的预测能力。通过交叉- 参考这些结果，我们计划将体外数据与体内数据相关联以建立IVIVC。

项目成果

Variability of Skin Pharmacokinetic Data: Insights from a Topical Bioequivalence Study Using Dermal Open Flow Microperfusion.

• DOI: 10.1007/s11095-020-02920-x
• 发表时间: 2020-09-28
• 期刊: Pharmaceutical research
• 影响因子: 3.7
• 作者: Bodenlenz M;Augustin T;Birngruber T;Tiffner KI;Boulgaropoulos B;Schwingenschuh S;Raney SG;Rantou E;Sinner F
• 通讯作者: Sinner F