On the processes limiting oral drug absorption when amorphous solid dispersions are administered after a high-calorie, high-fat meal: Sporanox® pellets.

OBJECTIVES: 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.

Understanding the Conditions Under Which Drugs are Transferred from the Stomach Through the Upper Small Intestine After a High-Calorie, High-Fat Meal.

Information on the conditions under which drugs are transferred from the stomach through the upper small intestine after a high-calorie, high-fat meal is very limited. To simulate the drug presence after disintegration and arrival in the antral region, paracetamol solution and Sporanox® amorphous solid dispersion pellets at two dose levels were administered to the antrum of 8 healthy adults 30 min after administration of a high-calorie, high-fat meal on a crossover basis. The overall median buffer capacity of antral contents was estimated to be 18.0 and 24.0 mmol/ml/ΔpH when titrating with NaOH and HCl, respectively. The corresponding values for the contents of upper the small intestine were 14.0 and 16.8 mmol/ml/ΔpH, respectively. The drug transfer process from the antrum through the upper small intestine occurred with apparent first-order kinetics. The best estimate for the antral emptying half-life was 39min and 45min for paracetamol and itraconazole, respectively, the apparent volume of contents of the upper small intestine was more than double compared with previously reported values in the fasted state, the half-life of drug elimination from the upper small intestine was similar to recent estimates for highly permeable drugs in the fasted state, and the apparent volume of antral contents during the first couple of hours post drug administration was 303mL. Information collected in this study could increase the reliability of in silico and/or in vitro modelling approaches applied in clinical drug development.

Leveraging the use of in vitro and computational methods to support the development of enabling oral drug products: An InPharma commentary.

Due to the strong tendency towards poorly soluble drugs in modern development pipelines, enabling drug formulations such as amorphous solid dispersions, cyclodextrins, co-crystals and lipid-based formulations are frequently applied to solubilize or generate supersaturation in gastrointestinal fluids, thus enhancing oral drug absorption. Although many innovative in vitro and in silico tools have been introduced in recent years to aid development of enabling formulations, significant knowledge gaps still exist with respect to how best to implement them. As a result, the development strategy for enabling formulations varies considerably within the industry and many elements of empiricism remain. The InPharma network aims to advance a mechanistic, animal-free approach to the assessment of drug developability. This commentary focuses current status and next steps that will be taken in InPharma to identify and fully utilize 'best practice' in vitro and in silico tools for use in physiologically based biopharmaceutic models.