(M1330-03-14) Apparent Danazol and Ketoconazole Solubility in the Upper Gastrointestinal Lumen after Administration of a Standard High-Calorie, High-Fat Meal and Its Estimation Using Biorelevant Media

Purpose: To measure apparent danazol and ketoconazole solubility in aspirates collected from the antrum and from the upper small intestine of healthy adults after administration of the meal typically administered in bioequivalence/bioavailability studies. To optimize the buffer capacity of FeSSGF-V2 (Pentafragka et al. 2020a), according to luminal data (Pentafragka et al. 2020b). To evaluate the usefulness of biorelevant media in estimating the apparent danazol and ketoconazole solubility in aspirates from the antrum and from the upper small intestine after administration of a standard high-calorie, high-fat meal.

Methods: The apparent danazol and ketoconazole solubility aspirates collected from the antrum and from the upper small intestine of healthy adults after a standard high-calorie (990 calories) high-fat (61% fat) meal (Pentafragka et al. 2020b) were measured. The buffer capacity of FeSSGF-V2 was optimized and FeSSGF-V2mod was proposed. Apparent danazol and ketoconazole solubility was measured in FeSSGF-V2, in FeSSGF-V2mod, in FEDGAS® pH=3 (FEDGAS_pH=3) , in FEDGAS® pH=3 with decreased presence of solubilizing agents to 1/2 and to 1/4 of that proposed by the supplier of FEDGAS® (biorelevant.com) i.e., FEDGAS_1/2,pH=3 and FEDGAS_1/4,pH=3, respectively, and in FeSSIF-V2. Each medium was evaluated at both Level I and Level II simulation of the luminal environment (Markopoulos, Andreas et al. 2015).

Results: For danazol, FeSSGF-V2, FeSSGF-V2mod and FEDGAS_pH=3 differences in buffering capacity had no impact on the apparent solubility. However, Level I simulation of gastric contents led to substantial underestimation of apparent intragastric danazol solubility in all cases. Level II simulation by using FeSSGF-V2 or FeSSGF-V2mod also led to underestimation of intragastric danazol solubility, presumably due to the small underestimation of intragastric lipid content with these media. Level II simulation by using FEDGAS_pH=3 , FEDGAS_1/2,pH=3 or FEDGAS_1/4,pH=3 led to substantial overestimation of danazol solubility. A linear relationship between the concentration of solubilizing agents FEDGAS_pH=3 and apparent danazol solubility was observed. For ketoconazole, FeSSGF-V2mod improved the estimation of apparent intragastric solubility. Level I and Level II simulations of gastric contents with FeSSGF-V2mod were equally sufficient. Data in FeSSGF-V2mod and in FEDGAS_1/4,pH=3 slightly overestimated apparent ketoconazole solubility in gastric aspirated. Apparent ketoconazole solubility did not increase linearly with the concentration of solubilizing agents in FEDGAS_pH=3, confirming the impact of pH on intragastric solubility of ketoconazole at pH values expected after the administration of the meal typically administered in bioequivalence/bioavailability studies. For both danazol and ketoconazole, data in Level I FeSSIF-V2 substantially underestimated the apparent solubility in the contents of upper small intestine. Although to a lesser degree, underestimation remained when Level II FeSSIF-V2 was employed for the estimation of danazol solubility, presumably due to the slight underestimation of luminal solubilizing agents in Level II FeSSIF-V2. In contrast, the use of Level II FeSSIF-V2 led to adequate simulation of the apparent ketoconazole solubility in the contents of upper small intestine in the fed state; apparent ketoconazole solubility is affected by both the lipid content of the medium and the partial ionization of ketoconazole.

Conclusion: For danazol, apparent solubility in the gastric contents after administration of the meal typically administered in bioequivalence/bioavailability studies is underestimated by data in FeSSGF-V2 or in FeSSGF-V2mod whereas it is overestimated by data FEDGAS_1/4,pH=3. For ketoconazole, apparent solubility in the gastric contents was slightly overestimated by data in FeSSGF-V2mod or data in FEDGAS_1/4,pH=3. The potential usefulness of optimization of solubilizing agents in FEDGAS_pH=3 is worth further investigation. FeSSIF-V2 inadequately simulates the presence of solubilizing agents in the upper small intestine and, based on data collected in this study, it may lead to underestimation of luminal solubility of compounds which are at least as lipophilic as danazol.

References: Markopoulos C, Andreas CJ, Vertzoni M, Dressman J, Reppas C. In-vitro simulation of luminal conditions for evaluation of performance of oral drug products: Choosing the appropriate test media. Eur J Pharm Biopharm. 93:173-82 (2015).
Pentafragka C, Vertzoni M, Dressman J, Symillides M, Goumas K, Reppas C. Characteristics of contents in the upper gastrointestinal lumen after a standard high-calorie high-fat meal and implications for the in vitro drug product performance testing conditions. Eur J Pharm Sci. 155:105535 (2020a).
Pentafragka C, Vertzoni M, Symillides M, Goumas K, Reppas C. Disposition of two highly permeable drugs in the upper gastrointestinal lumen of healthy adults after a standard high-calorie, high-fat meal. Eur J Pharm Sci. 149:105351 (2020b).