超越五种前药规则的药物开发挑战：ABBV-167（Venetoclax 磷酸盐前药）的案例研究,Molecular Pharmaceutics

当前位置： X-MOL 学术 › Mol. Pharmaceutics › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

超越五种前药规则的药物开发挑战：ABBV-167（Venetoclax 磷酸盐前药）的案例研究
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2023-09-26 , DOI: 10.1021/acs.molpharmaceut.3c00675
Richard Hong ₁ , Haichen Nie ₁ , Rodger F Henry ₁ , Sean M Garner ₁ , Nathaniel D Catron ₁ , Russell L Hertzler ₁ , Andrew J Souers ₁ , Ahmad Y Sheikh ₁ , Shuang Chen ₁

Affiliation

ABBV-167 是 BCL-2 抑制剂 Venetoclax 的磷酸盐前药，最近进入临床，作为高剂量适应症患者减轻药物负担的替代方法。ABBV-167 的水溶性显着增强，可在结晶片剂中实现高载药量，并且在 I 期临床研究中给药时，维奈托克暴露量与作为无定形固体分散体给药的等效剂量相当。为了能够进入临床，我们对这种超越五规则（bRo5）前药的 CMC 开发方面进行了全面评估。添加磷酸盐部分会导致过于复杂的化学形态和具有显着物理化学稳定性缺陷的固体形态。实验和计算方法相结合，包括微电子衍射 (MicroED)、全散射、片剂比色法、有限元和分子动力学建模，用于了解 CMC 在原料药和产品制造和储存中的可开发性。研究发现，该前药的化学结构特征和松散的晶体堆积是其制造过程中结晶度损失的原因，进而导致高固态化学反应性和较差的保质期稳定性。ABBV-167 案例体现了复杂化学物质（例如 bRo5 磷酸盐前药）在原料药和药品生产和储存过程中产生重大影响的关键 CMC 开发挑战。

"点击查看英文标题和摘要"

Pharmaceutical Development Challenges in a Beyond Rule of Five Prodrug: Case Study of ABBV-167, Phosphate Prodrug of Venetoclax

ABBV-167, a phosphate prodrug of BCL-2 inhibitor venetoclax, was recently progressed into the clinic as an alternative means of reducing pill burden for patients in high-dose indications. The dramatically enhanced aqueous solubility of ABBV-167 allowed for high drug loading within a crystalline tablet and, when administered in phase I clinical study, conferred venetoclax exposure commensurate with the equivalent dose administered as an amorphous solid dispersion. In enabling the progression into the clinic, we performed a comprehensive evaluation of the CMC development aspects of this beyond the rule of five (bRo5) prodrug. Adding a phosphate moiety resulted in excessively complex chemical speciation and solid form landscapes with significant physical-chemical stability liabilities. A combination of experimental and computational methods including microelectron diffraction (MicroED), total scattering, tablet colorimetry, finite element, and molecular dynamics modeling were used to understand CMC developability across drug substance and product manufacture and storage. The prodrug’s chemical structural characteristics and loose crystal packing were found to be responsible for the loss of crystallinity during its manufacturing, which in turn led to high solid-state chemical reactivity and poor shelf life stability. The ABBV-167 case exemplifies key CMC development challenges for complex chemical matter such as bRo5 phosphate prodrugs with significant ramifications during drug substance and drug product manufacturing and storage.

更新日期：2023-09-26

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南