Purpose

To use physiologically-based pharmacokinetic (PBPK) modelling to explore the food effect of different DNX hydrobromide (HBr) hemihydrate salt tablet formulations using biorelevant dissolution.

Methods

Compendial dissolution using a paddle method and TIM-1 biorelevant dissolution were performed and incorporated into a previously reported PBPK model. A two-part clinical study evaluated tablet formulations in the fasted/fed (high fat) state (Part A), and the impact of food (fasted/normal/high fat) and Proton Pump Inhibitor (PPI) co-administration for a selected formulation; as well as a formulation containing DNX HBr in the monohydrate state (Part B).

Results

TIM-1 data showed that the fed state bioaccessibility of DNX was significantly decreased compared to the fasted state with no significant differences between formulations. Dosed with normal/high fat food the selected formulation showed comparable exposure and a modest increase in DNX systemic PK was observed with PPI dependent on meal type. Under fed conditions DNX systemic exposure was comparable for the monohydrate and hemihydrate formulations. The integration of biorelevant TIM-1 data into the PBPK model led to the successful simulation of a DNX negative food effect.

Conclusions

Interactions between DNX and food components are the likely the source of the negative food effect via micellar entrapment, ion pairing and/or meal induced viscosity changes.

中文翻译：

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Danirixin 的负面食物效应：使用 PBPK 建模探索配方和膳食类型对临床 PK 的影响

目的

使用基于生理学的药代动力学 (PBPK) 模型，利用生物相关溶出度探索不同 DNX 氢溴酸盐 (HBr) 半水盐片剂制剂的食物效应。

方法

进行了使用桨法的药典溶出度和 TIM-1 生物相关溶出度，并将其纳入先前报道的 PBPK 模型。一项由两部分组成的临床研究评估了禁食/进食（高脂肪）状态（A 部分）下的片剂配方，以及食物（禁食/正常/高脂肪）和质子泵抑制剂 (PPI) 联合给药对所选药物的影响公式; 以及包含一水合物状态的 DNX HBr 的配方（B 部分）。

结果

TIM-1 数据显示，与禁食状态相比，DNX 的进食状态生物可及性显着降低，配方之间没有显着差异。与正常/高脂肪食物一起服用时，所选配方显示出相当的暴露量，并且观察到 DNX 全身 PK 适度增加，而 PPI 取决于膳食类型。在喂食条件下，一水合物和半水合物制剂的 DNX 全身暴露量相当。将生物相关 TIM-1 数据整合到 PBPK 模型中，成功模拟了 DNX 负面食物效应。

结论

DNX 和食物成分之间的相互作用可能是通过胶束捕获、离子配对和/或膳食引起的粘度变化产生负面食物影响的来源。