(W1130-01-02) Itraconazole Concentrations in the Colloidal Aqueous Phase of Contents of Upper Small Intestine after the Standard High-Calorie High-Fat Meal and Their Relevance to Itraconazole Plasma Levels

Purpose: The first objective was to measure concentrations of itraconazole administered as single doses of 100 mg and 200 mg amorphous solid dispersion pellets (Sporanox® capsules) in the colloidal aqueous phase of contents of upper small intestine, after the standard meal and to evaluate their relevance to previously observed dose-related differences in plasma levels after the standard meal [1-4]. The second objective was to evaluate whether data collected after the 200 mg dose in this study and previously in the fasted state [5] reflect food effects on plasma levels [4].

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 aqueous solution. Up to about 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 itraconazole capsule(s). Aspirates were centrifuged (5 min, 37 °C, 15,486 g) and the colloidal aqueous phase was stored at -20 °C until measuring the drug content.

Results: Mean (median) AUC_0-4h values after the 100 mg and the 200 mg dose were 325 (263) µg mL^-1 min^-1 (n=5) and 454 (423) µg mL^-1 min^-1 (n=3), i.e. mean(median) AUC_{0-4h,100lumen,fed} / AUC_{0-4h,200lumen,fed} = 0.71(0.62). Based on publicly available information, single itraconazole doses administered as Sporanox® capsules after the standard meal result in highly variable drug levels with mean plasma AUC_0-4h values for the 100 mg dose 169 ng mL^-1 h^-1 (grand mean from three separate clinical studies [1][2][3]) and for the 200 mg dose 349 ng mL^-1 h^-1 [4]); mean AUC_{0-4h,100plasma,fed} / mean AUC_{0-4h,200plasma,fed} = 0.48. Mean itraconazole concentrations in the colloidal aqueous phase of contents of upper small intestine measured after the 200 mg dose in this study and previously in the fasted state [5] result in mean AUC_{0-4h,200lumen} values 454 µg mL^-1 min^-1 (n=3), and 1129 µg mL^-1 min^-1 (n=5), respectively, i.e mean AUC_{0-4h,200lumen,fed} / mean AUC_{0-4h,200lumen,fasted} = 0.40. Based on publicly available information, single 200 mg itraconazole dose administered as Sporanox® capsules after the standard meal and in the fasted state results in mean AUC_{0-4h,200plasma,fed} / mean AUC_{0-4h,200plasma,fasted} = 1.35 (crossover study, n=28 [4]).

Conclusion: Data from this study suggest that during the first 4 hours after Sporanox® administration dose related differences in colloidal itraconazole concentrations in upper small intestine after the standard meal are, on average, in line with previously observed differences in plasma itraconazole concentrations after the standard meal. In contrast, differences in colloidal itraconazole concentrations between the fasted and the fed state do not reflect differences in plasma levels after the 200 mg dose.

References: 1. Zimmermann et al. Eur J Clin Pharmacol. 46:147 (1994)
2. Woo et al. Eur J Pharm Sci. 33:159 (2008)
3. Dragojević-Simić et al. Expert Opin Drug Metab Toxicol. 14:979 (2018)
4. Barone et al. Antimicrob Agents Chemother. 37:778 (1993)
5. Brouwers et al. Int J Pharm. 525:211 (2017)

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.