Bioequivalence of topical drug products: in vitro - in vivo correlations

项目概要/摘要。本项目响应了资助机会RFA-FD-13-016，“体外 局部皮肤病产品的释放试验（U 01）"。制定适当的方法来确定 局部皮肤病产品的生物等效性（BE）是食品和药物管理局的一个重要目标， 管理局（FDA）。虽然该机构已经确定了有限的情况-例如， 含有相同量的相同非活性成分-其中临床终点的替代品 生物等效性研究是可能的，FDA在确定替代试验方面面临着长期的挑战 预测组成不同的制剂是否导致 等效的药物递送到皮肤和穿过皮肤。 因此，本项目的长期目标是证明与 局部药物产品的性能与体内结果相关，因此， 方法可以可靠和可重复地用于建立（不）等效性， 含有相同活性药物成分（API）的制剂用于皮肤。 拟议的研究战略主要旨在检验三个假设： 1.该局部BE评估可以通过使用适当选择的体外和/或体外细胞因子来完成。 体内替代试验。 2.所有的替代检验都有局限性，但它们并不都有相同的局限性;因此， 一个测试的结果与另一个测试的结果相辅相成。 3.选择的测试取决于制剂的复杂性以及非活性成分是否 产品中的成分在数量上和/或组成上是等同的。 该项目分为两个阶段，各有具体目标：[A]初步的、密集的、为期12个月的 工作计划的重点是益康唑、戊酸倍他米松（BMV）和双氯芬酸。用于抗真菌 和BMV，以生成体外皮肤渗透和释放测试数据，用于与 已发表的体内数据，特别是两者的皮肤药代动力学（DPK）信息，以及血管收缩 皮质类固醇的测量结果对于双氯芬酸，补充体内DPK实验，血液水平 使用高灵敏度液相色谱/质谱法进行测定， 这些结果与体外皮肤渗透和释放试验研究。[B]进一步的4年调查， 适当时体外试验的可预测性，并确定更简单的体内方法的潜力， 使用临床试验进行局部（非）等效性默认评估的替代替代品。一个系统 将对几类关键的局部药物产品进行检查，包括但不限于 利多卡因、曲安奈德、维甲酸、阿昔洛韦和甲硝唑。

Project Summary/Abstract. This project responds to the Funding Opportunity, RFA-FD-13-016, "In vitro release tests for topical dermatological products (U01)". The development of appropriate methods to determine bioequivalence (BE) of topical dermatological products is a significant objective of the Food & Drug Administration (FDA). While the agency has identified limited situations - for example when formulations contain the same inactive ingredients in the same amounts - in which alternatives to clinical endpoint bioequivalence studies may be possible, the FDA has a long-standing challenge to determine surrogate test methods (including in vitro techniques) to predict whether formulations, which differ in composition, result in equivalent drug delivery to and across the skin. The long-term goal of this project, therefore, is to demonstrate that in vitro measurements related to the performance of topical drug products are correlated with in vivo outcomes, such that simpler experimental approaches can be reliably and reproducibly used for the establishment of (in)equivalence between formulations containing the same active pharmaceutical ingredient (API) for application to the skin. The proposed research strategy broadly aims to test three hypotheses: 1. That topical BE assessment can be accomplished through the use of appropriately selected in vitro and/or in vivo surrogate tests. 2. That all surrogate tests have limitations but that they do not all have the same limitations; it follows that the results of one test complement those of another. 3. That the test(s) chosen depend on the complexity of the formulation and whether or not the inactive ingredients in the product are quantitatively and/or compositionally equivalent. The project has been designed in two phases, with individual specific aims: [A] An initial, intensive, 12-month program of work focused on econazole, betamethasone valerate (BMV) and diclofenac. For the anti-fungal and BMV, to generate in vitro skin penetration and release test data for comparison and correlation with published in vivo data, specifically, dermatopharmacokinetic (DPK) information for both, and vasoconstriction measurements for the corticosteroid. For diclofenac, to complement in vivo DPK experiments with blood level determinations using highly sensitive liquid chromatography/mass spectrometry methods and to correlate these results with in vitro skin penetration and release test studies. [B] A further 4-year investigation to validate the predictability of in vitro tests when appropriate, and to identify the potential of simpler in vivo approaches as alternative surrogates for the default assessment of topical (in)equivalence using a clinical trial. A systematic examination of several key classes of topical drug products will be undertaken including, but not limited to lidocaine, triamcinolone acetonide, tretinoin, acyclovir and metronidazole.