(M1330-01-04) Characterizing the Drug Gastrointestinal Transfer Process after Disintegration of Solid Dose Units in the Fed State

Purpose: To characterize the gastrointestinal drug transfer process after disintegration of solid dose units in the fed state by monitoring the paracetamol and itraconazole presence in the antrum of the stomach and in the lumen of upper small intestine and building on recently published relevant information [1].

Methods: Eight healthy male adult volunteers (27-56 y) participated in a two-phase clinical intubation study. The study was performed, after receiving approvals by the Scientific Committee (AP 3814 / 16-2-2022) and the Executive Committee (AP 12847/25-5-2022) of the Hospital. At each phase, the volunteer reported to the hospital in the morning after fasting for at least 12 hours and was intubated with a naso-gastro-intestinal tube. The volunteer was then administered directly into the antrum a homogenized high-fat high-calorie meal (989 kcal, 15 % proteins, 24 % carbohydrates, and 61 % fat). Thirty minutes after the initiation of meal administration, the contents of one Sporanox® capsule (100 mg itraconazole, Phase 1) or the contents of two Sporanox® capsules (200 mg itraconazole, Phase 2) were administered to the antrum of the volunteer with 240 mL paracetamol solution in water (1.25mg/ml). Up to about 11 mL of antral contents were aspirated at 20, 45, 75, 105, 135 and 195 min and up to 11 mL of contents from the upper small intestine were aspirated at 10, 30, 60, 90, 120, 150, 180, 210, and 240 min after administration of the drugs. Aspirates were stored at -20 °C until measuring the total drug amount per volume in each aspirated sample. Apparent first-order drug input and drug elimination kinetics in the lumen of upper small intestine were assumed. The transfer of itraconazole through the upper small intestine was simulated by assuming a lag time for the initiation of gastric emptying process; without this assumption physiologically not relevant estimates for volume of contents of upper small intestine and elimination rate constant from upper small intestine were estimated. All simulations were performed with Phoenix (Certara Phoenix v8.3.5). For both drugs the adequacy of simulation was evaluated against total drug amount/volume data collected from both phases of the study (n=16 data sets for gastric aspirates and n=16 data sets for intestinal aspirates); as itraconazole differed between the two phases, itraconazole amount/volume data were dose-normalized.

Results: The estimate for paracetamol gastric emptying rate constant estimated from gastric data coincided with the estimate from the data in the upper small intestine confirming that when no major alterations in intragastric volume during the first couple hours post-dosing, no drug is absorbed from the gastric mucosa, and well-stirred conditions can be assumed, the profile of total drug amount per volume of gastric content vs. time post-dosing reflects the drug gastric emptying process [1]. Itraconazole data from the stomach were highly variable and not useful for the description of the gastric emptying process. Assuming apparent first-order input and elimination kinetics in the lumen of upper small intestine, the values of drug gastric emptying rate constant, volume of contents in the upper small intestine and drug elimination rate constant from the upper small intestine estimated by using the paracetamol data were similar with those estimated the itraconazole data (Table 1). Difference between paracetamol and itraconazole in the elimination rate constant from the upper small intestine could be attributed to the higher itraconazole lipophilicity.

Conclusion: Data collected in this work provide a basis for the description of the gastrointestinal drug transfer process after the standard meal and are expected to facilitate the design of biorelevant in vitro methodologies for the evaluation of intraluminal fate of drugs after intragastric disintegration in the fed state.

References: [1] Pentafragka et al. Eur J Pharm Sci 149:105351 (2020)

Acknowledgements: This work has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 955756.

Table 1