目的:1)确定当Sporanox®无定形固体分散体(ASD)颗粒从胃通过小肠上部转移时,限制伊曲康唑到达肠上皮的过程,在高热量之后,高脂肪餐。2)评估小肠上部内容物的胶体相中的伊曲康唑浓度是否可用于评估进食状态下的剂量效应和食物对血浆水平的影响。
方法:伊曲康唑浓度,表观粘度,和溶解能力是在最近在健康成年人中进行的临床研究中收集的上消化道腔的抽出物中测量的。伊曲康唑在血浆中的浓度,在高热量高脂肪膳食和Sporanox®ASD颗粒后,健康成年人的小肠上部的内容物,在禁食状态下服用Sporanox®ASD颗粒后,用于实现第二个目标。
结果:当Sporanox®ASD颗粒(最多200mg)从胃通过小肠上部转移时,在高热量之后,高脂肪餐,伊曲康唑在胶体相或胶束相中的上层小肠内容物的浓度是不饱和的,在大多数情况下。在高热量给药后的第一个3小时内,高脂肪餐,剂量的影响(200mgvs.100mg)对小肠上部内容物胶体相中伊曲康唑浓度的影响似乎低估了剂量对血浆水平的影响。当Sporanox®ASD颗粒在高热量后服用时,200毫克剂量水平的高脂肪膳食,伊曲康唑在上层小肠含水物质胶体相中的浓度为,平均而言,低于禁食状态下的水平。
结论:当Sporanox®ASD颗粒在高热量摄入后从胃转移到小肠上部时,高脂肪餐,伊曲康唑到达肠上皮似乎受到其到达小肠上部含水物质胶态相的限制。剂量的影响(100mgvs.200毫克)高热量后的血浆水平,高脂肪膳食和Sporanox®颗粒的胃肠道转移期间需要考虑系统前伊曲康唑代谢。在200毫克的剂量水平,在考虑到Sporanox®ASD颗粒胃肠转移期间禁食和进食状态之间的上部小肠内容物的体积差异后,伊曲康唑在小肠上部含水物质的胶体相中的浓度表明食物对平均血浆水平有轻微的负面影响;已发表的临床数据尚无定论。
OBJECTIVE: 1) Identify processes limiting the arrival of itraconazole at the intestinal epithelium when Sporanox® amorphous solid dispersion (ASD) pellets are transferred from the stomach through the upper small intestine, after a high-calorie, high-fat meal. 2) Evaluate whether itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine are useful for the assessment of dose effects in the fed state and food effects on plasma levels.
METHODS: Itraconazole concentrations, apparent viscosity, and solubilization capacity were measured in aspirates from the upper gastrointestinal lumen collected during a recently performed clinical study in healthy adults. Published itraconazole concentrations in plasma, after a high-calorie high-fat meal and Sporanox® ASD pellets, and in contents of the upper small intestine of healthy adults, after administration of Sporanox® ASD pellets in the fasted state, were used to achieve the second objective.
RESULTS: When Sporanox® ASD pellets (up to 200 mg) are transferred from the stomach through the upper small intestine, after a high-calorie, high-fat meal, itraconazole concentrations in the colloidal phase or the micellar phase of aqueous contents of the upper small intestine are unsaturated, in most cases. During the first 3 h post-dosing after a high-calorie, high-fat meal, the impact of dose (200 mg vs. 100 mg) on itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine seems to underestimate the impact of dose on plasma levels. When Sporanox® ASD pellets are administered after a high-calorie, high-fat meal at the 200 mg dose level, itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine are, on average, lower than those achieved in fasted state.
CONCLUSIONS: When Sporanox® ASD pellets are transferred from the stomach to the upper small intestine after a high-calorie, high-fat meal, itraconazole\'s arrival at the intestinal epithelium seems to be limited by its arrival at the colloidal phase of aqueous contents of the upper small intestine. The impact of dose (100 mg vs. 200 mg) on plasma levels after a high-calorie, high-fat meal and during the gastrointestinal transfer of Sporanox® pellets requires consideration of pre-systemic itraconazole metabolism. At the 200 mg dose level, after taking into consideration differences in the volume of the contents of the upper small intestine between the fasted and the fed state during the gastrointestinal transfer of Sporanox® ASD pellets, itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine suggest a mild negative food effect on average plasma levels; published clinical data are inconclusive.