Developmental Therapeutics Program, Children's Hospital Los Angeles, Children's Center for Cancer and Blood Diseases, Los Angeles, CA 90027, USA.
Expert Opin Investig Drugs. 2012 Apr;21(4):489-500. doi: 10.1517/13543784.2012.664635. Epub 2012 Feb 24.
Pre-exposure prophylaxis (PrEP) is an evolving new approach to prevention of sexually transmitted HIV-1 that employs antiretroviral (ARV) agents prior to potential HIV-1 exposure in an attempt to reduce the likelihood of HIV-1 infection postexposure. The identification of new ARV agents with potent activity against multidrug-resistant HIV remains an unmet and urgent challenge in the field of PrEP.
This article reviews the preclinical and early clinical activity and safety profile of stampidine, a novel antiretroviral (ARV) drug candidate that exhibits remarkable subnanomolar to low nanomolar in vitro antiretroviral potency against genotypically and phenotypically nucleoside reverse transcriptase inhibitor (NRTI)-resistant primary clinical HIV isolates, non-nucleoside RT-resistant HIV-1 isolates. Stampidine has a favorable pharmacokinetic profile in mice, rats, dogs and cats with 25 or 50 mg/kg tolerable dose levels yielding micromolar plasma concentrations that are 1000-fold higher than its in vitro IC(50) value against HIV. Stampidine has a favorable, safety profile in mice, rats, dogs and cats and it showed significant in vivo ARV activity in HIV-infected Hu-PBL-SCID mice as well as FIV-infected domestic cats. Furthermore, it did not cause any maternal toxicity, developmental toxicity or teratogenicity in rabbits treated at 10 - 40 mg/kg/day dose levels. In a recently completed first-in-human Phase I clinical trial, stampidine did not cause dose-limiting toxicity at single dose levels ranging from 5 to 25 mg/kg.
The favorable safety and activity profile of stampidine warrants its further development as a promising next-generation PrEP candidate to prevent the sexual transmission of HIV-1. The discovery of stampidine as a potent antiretroviral agent represents a significant step forward in the development of effective therapeutic as well as preventive strategies against HIV/AIDS.
暴露前预防（PrEP）是一种新的预防性治疗方法，通过在潜在的 HIV-1 暴露之前使用抗逆转录病毒（ARV）药物，试图降低暴露后 HIV-1 感染的可能性。在 PrEP 领域，发现具有针对多药耐药 HIV 强大活性的新型 ARV 药物仍然是一个未满足的紧迫挑战。
本文综述了新型抗逆转录病毒（ARV）药物候选物 stampidine 的临床前和早期临床活性和安全性特征。Stampidine 对基因型和表型核苷逆转录酶抑制剂（NRTI）耐药的原发性临床 HIV 分离株、非核苷 RT 耐药的 HIV-1 分离株具有显著的亚纳摩尔至低纳摩尔的体外抗逆转录病毒效力。Stampidine 在小鼠、大鼠、狗和猫中具有良好的药代动力学特征，25 或 50mg/kg 的耐受剂量水平可产生微摩尔血浆浓度，是其对 HIV 的体外 IC50 值的 1000 倍以上。Stampidine 在小鼠、大鼠、狗和猫中具有良好的安全性特征，在感染 HIV 的 Hu-PBL-SCID 小鼠以及感染 FIV 的家猫中表现出显著的体内 ARV 活性。此外，在 10-40mg/kg/天剂量水平治疗的兔子中，它没有引起任何母体毒性、发育毒性或致畸性。在最近完成的首次人体 I 期临床试验中，Stampidine 在 5-25mg/kg 的单剂量水平下没有引起剂量限制性毒性。
Stampidine 的良好安全性和活性特征使其成为一种有前途的下一代 PrEP 候选药物，可预防 HIV-1 的性传播。Stampidine 作为一种有效的抗逆转录病毒药物的发现，代表了在开发针对 HIV/AIDS 的有效治疗和预防策略方面向前迈出了重要的一步。
