Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Butler University, Indianapolis, IN, 46208, USA.
Synthetic Molecule Design and Development, Lilly Research Labs, Eli Lilly & Company, Indianapolis, IN, 46285, USA.
Pharm Res. 2022 Sep;39(9):2217-2226. doi: 10.1007/s11095-022-03321-y. Epub 2022 Jul 1.
pH-dependent drug-drug interactions (DDIs) with poorly soluble, weakly basic drugs may lead to clinical implications. Dasatinib is a tyrosine kinase inhibitor with reduced absorption in patients on acid-reducing agents (ARAs). The objective of this study is to investigate the influence of gastric pH on dasatinib supersaturation and determine if vitamin C (L-ascorbic acid) can improve dasatinib concentrations under simulated hypochlorhydric gastric conditions.
A dynamic, in vitro, multi-compartment, simulated stomach duodenum (SSD) model mimicking fluid volumes and transfer rates was used to investigate the concentration of BCS class IIb drugs versus time curves. Dasatinib and lamotrigine were explored under normal, fasted, simulated gastric fluids (pH 2) (FaSGF), hypochlorhydric simulated gastric fluids (pH 4.5) (FaSGF) and FaSGF with 1000 mg of vitamin C.
Significant supersaturation of dasatinib was observed in the duodenum compartment of the SSD model in FaSGF. A 90% reduction in dasatinib AUC was observed in FaSGF. Upon addition of vitamin C to FaSGF, drug concentrations were restored to those observed in FaSGF. Lamotrigine AUC in the duodenal compartment were similar in both FaSGF and FaSGF. The in vitro trends observed for dasatinib and lamotrigine are reflective of the trends observed in vivo in subjects receiving treatment with ARAs.
The SSD model serves as a good in vitro tool for assessing the effect of pH-dependent DDIs on bioavailability of weakly basic drugs with solubility/ dissolution limited absorption. Vitamin C provides a promising approach for improving bioavailability of poorly soluble, weakly basic drugs in hypochlorhydric patients.
与溶解度低、碱性弱的药物相关的 pH 依赖性药物-药物相互作用（DDI）可能具有临床意义。达沙替尼是一种酪氨酸激酶抑制剂，在使用胃酸抑制剂（ARA）的患者中其吸收减少。本研究的目的是研究胃 pH 值对达沙替尼超饱和度的影响，并确定维生素 C（L-抗坏血酸）是否可以在模拟低胃酸胃条件下提高达沙替尼的浓度。
使用动态、体外、多室、模拟胃十二指肠（SSD）模型来模拟体积和转移率，以研究 BCS 类 IIb 药物的浓度与时间曲线。在正常、空腹、模拟胃液（pH 2）（FaSGF）、低胃酸模拟胃液（pH 4.5）（FaSGF）以及 FaSGF 中添加 1000mg 维生素 C 的条件下研究达沙替尼和拉莫三嗪。
在 FaSGF 中 SSD 模型的十二指肠隔室中观察到达沙替尼的显著超饱和度。在 FaSGF 中观察到达沙替尼 AUC 减少了 90%。在 FaSGF 中添加维生素 C 后，药物浓度恢复到 FaSGF 中观察到的浓度。FaSGF 和 FaSGF 中拉莫三嗪的 AUC 在十二指肠隔室中相似。在接受 ARA 治疗的患者中观察到的达沙替尼和拉莫三嗪的体内趋势反映了在 SSD 模型中观察到的体外趋势。
SSD 模型是评估 pH 依赖性 DDI 对弱碱性药物生物利用度的溶解度/溶解有限吸收的良好体外工具。维生素 C 为改善低胃酸患者中溶解度差、碱性弱的药物的生物利用度提供了一种有前景的方法。
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