PDF(Pubmed)
Abstract：
The development of numerous drugs is often arrested at clinical testing stages, due to their unfavorable biopharmaceutical characteristics. It is the case of fenretinide (4-HPR), a second-generation retinoid, that demonstrated promising in vitro cytotoxic activity against several cancer cell lines. Unfortunately, response rates in early clinical trials with 4-HPR did not confirm the in vitro findings, mainly due to the low bioavailability of the oral capsular formulation that was initially developed. Capsular 4-HPR provided variable and insufficient drug plasma levels attributable to the high hepatic first-pass effect and poor drug water solubility. To improve 4-HPR bioavailability, several approaches have been put forward and tested in preclinical and early-phase clinical trials, demonstrating generally improved plasma levels and minimal systemic toxicities, but also modest antitumor efficacy. The challenge is thus currently still far from being met. To redirect the diminished interest of pharmaceutical companies toward 4-HPR and promote its further clinical development, this manuscript reviewed the attempts made so far by researchers to enhance 4-HPR bioavailability. A comparison of the available data was performed, and future directions were proposed.
摘要：
许多药物的开发经常在临床测试阶段被阻止，由于其不利的生物制药特性。这就是fenretinide（4-HPR）的情况，第二代类维生素A，这证明了对几种癌细胞系的有希望的体外细胞毒性活性。不幸的是,4-HPR早期临床试验的反应率没有证实体外研究结果，主要是由于最初开发的口服胶囊制剂的低生物利用度。胶囊4-HPR提供了可变和不足的药物血浆水平，这归因于高的肝首过效应和不良的药物水溶性。为了提高4-HPR的生物利用度，已经提出了几种方法，并在临床前和早期临床试验中进行了测试，显示血浆水平普遍改善，全身毒性最小，而且抗肿瘤疗效适中。因此，这一挑战目前仍远未得到解决。为了将制药公司减少的兴趣转向4-HPR，并促进其进一步的临床发展，这篇手稿回顾了研究人员迄今为提高4-HPR生物利用度所做的尝试.对现有数据进行了比较，并提出了未来的方向。
