Paquette Sara Montminy, Dawit Had, Hickey Magali B, Merisko-Liversidge Elaine, Almarsson Orn, Deaver Daniel R
Alkermes, Inc., 852 Winter Street, Waltham, Massachusetts, 02451, USA,
Pharm Res. 2014 Aug;31(8):2065-77. doi: 10.1007/s11095-014-1308-4. Epub 2014 Feb 21.
Long-acting injectables (LAIs) are increasingly recognized as an effective therapeutic approach for treating chronic conditions. Many LAIs are formulated to create a poorly soluble depot from which the active agent is delivered over time. This long residing depot can cause localized chronic-active inflammation in the tissue, which has not been well defined in the literature. The purpose of this work is to establish an experimental baseline for describing these responses.
Non-human primates and rodents were used to examine the response to LAI formulations of two clinically relevant atypical antipsychotics, aripiprazole monohydrate and olanzapine pamoate monohydrate.
A foreign body response develops with elevations of key cytokines such as IL-1α, IL-1β, TNFα, and IL6 at the site of injection. However, the tissue response for the two atypical antipsychotics compounds diverge as evidenced by quantitative differences observed in cytokine levels at various time points after dosing.
Our studies show that, while the drugs are in the same therapeutic class, the response to each of these compounds can be distinguished qualitatively and quantitatively, supporting the idea that the injection site reaction involves a multiplicity of factors including the properties of the compound and cellular dynamics at the site of injection.
长效注射剂（LAIs）日益被认为是治疗慢性病的一种有效治疗方法。许多长效注射剂的配方旨在形成一种难溶性储库，活性药物可从该储库中随时间释放。这种长期存在的储库可在组织中引起局部慢性活动性炎症，而这在文献中尚未得到很好的界定。这项工作的目的是建立一个用于描述这些反应的实验基线。
使用非人类灵长类动物和啮齿动物来研究对两种临床相关的非典型抗精神病药物（阿立哌唑一水合物和奥氮平棕榈酸酯一水合物）的长效注射剂配方的反应。
在注射部位出现异物反应，关键细胞因子如IL-1α、IL-1β、TNFα和IL6水平升高。然而，两种非典型抗精神病药物化合物的组织反应有所不同，给药后不同时间点细胞因子水平的定量差异证明了这一点。
我们的研究表明，虽然这些药物属于同一治疗类别，但对每种化合物的反应在定性和定量上都可以区分，这支持了注射部位反应涉及多种因素的观点，包括化合物的性质和注射部位的细胞动力学。
