Negative Food Effect of Danirixin: Use of PBPK Modelling to Explore the Effect of Formulation and Meal Type on Clinical PK
Negative Food Effect of Danirixin: Use of PBPK Modelling to Explore the Effect of Formulation and Meal Type on Clinical PK
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DOI：
10.1007/s11095-020-02948-z
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发表时间：
2020-10-29
影响因子：
3.7
通讯作者：
Ambery, Claire
中科院分区：
文献类型：
--
作者：
Lloyd, Richard S.;Hingle, Martin I.;Ambery, Claire
PurposeTo使用生理为基础的药代动力学（PBPK）建模，以探讨不同的DNX氢溴酸盐（HBr）半水合物盐片剂配方使用biorealeddissolution.MethodsCompendial溶解桨法和TIM-1 biorealeddissolution进行，并纳入到以前报道的PBPK模型的食物效应。一项由两部分组成的临床研究评价了空腹/餐后受试者中的片剂制剂（高脂肪）状态（A部分），以及食物的影响（禁食/正常/高脂肪）和质子泵抑制剂（PPI）共同施用;以及含有一水合物状态的DNX HBr的制剂（部分B）。1数据显示，与禁食状态相比，DNX的进食状态生物可及性显著降低，制剂之间无显著差异。在正常/高脂肪食物下给药，所选制剂显示出相当的暴露量，并且观察到依赖于膳食类型的PPI的DNX全身PK适度增加。在进食条件下，DNX一水合物和半水合物制剂的全身暴露相当。整合的生物相关TIM-1的数据到PBPK模型导致成功模拟DNX负食品effect. ConclusionsDNX和食品成分之间的相互作用是可能的来源，通过胶束截留，离子配对和/或膳食引起的粘度变化的负食品效应。
PurposeTo use physiologically-based pharmacokinetic (PBPK) modelling to explore the food effect of different DNX hydrobromide (HBr) hemihydrate salt tablet formulations using biorelevant dissolution.MethodsCompendial 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).ResultsTIM-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.ConclusionsInteractions 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.