Departments of Small Molecule Pharmaceutical Sciences, Genentech, Inc., One DNA Way, South San Francisco, California 94080.
Departments of Small Molecule Pharmaceutical Sciences, Genentech, Inc., One DNA Way, South San Francisco, California 94080.
J Pharm Sci. 2019 Jun;108(6):1934-1943. doi: 10.1016/j.xphs.2019.01.004. Epub 2019 Jan 11.
Solubilization of new chemical entities for toxicity assessment must use excipients that do not negatively impact drug pharmacokinetics and toxicology. In this study, we investigated the tolerability of a model freebase compound, GDC-0152, solubilized by pH adjustment with succinic acid and complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) to enable intravenous use. Solubility, critical micelle concentration, and association constant with HP-β-CD were determined. Blood compatibility and potential for hemolysis were assessed in vitro. Local tolerability was assessed after intravenous and subcutaneous injections in rats. A pharmacokinetic study was conducted in rats after intravenous bolus administration. GDC-0152 exhibited pH-dependent solubility that was influenced by self-association. The presence of succinic acid increased solubility in a concentration-dependent manner. HP-β-CD alone also increased solubility, but the extent of solubility enhancement was significantly lower than succinic acid alone. Inclusion of HP-β-CD in the solution of GDC-0152 improved blood compatibility, reduced hemolytic potential by ∼20-fold in vitro, and increased the maximum tolerated dose to 80 mg/kg.
新化学实体的增溶用于毒性评估必须使用不会对药物药代动力学和毒理学产生负面影响的赋形剂。在这项研究中，我们研究了模型游离碱化合物 GDC-0152 的耐受性，该化合物通过与琥珀酸的 pH 调节以及与羟丙基-β-环糊精（HP-β-CD）的络合来增溶，以实现静脉内使用。测定了溶解度、临界胶束浓度和与 HP-β-CD 的缔合常数。在体外评估了血液相容性和潜在的溶血作用。在大鼠中进行了静脉内和皮下注射后的局部耐受性评估。在大鼠中进行了静脉推注后的药代动力学研究。GDC-0152 表现出 pH 依赖性溶解度，其受自缔合影响。琥珀酸的存在以浓度依赖性方式增加了溶解度。单独的 HP-β-CD 也增加了溶解度，但溶解度的增强程度明显低于单独的琥珀酸。将 HP-β-CD 包含在 GDC-0152 的溶液中提高了血液相容性，在体外将溶血潜力降低了约 20 倍，并将最大耐受剂量提高到 80mg/kg。
