Department of Pharmacy
Library of the School of Science

2022-12-08

2022

Kostantini Christina

Maria Vertzoni, Associate Professor, Department of Pharmacy, National and Kapodistrian University of Athens, Greece
Christos Reppas, Professor, Department of Pharmacy, National and Kapodistrian University of Athens, Greece
Paraskevas Dallas, Assistant Professor, Department of Pharmacy, National and Kapodistrian University of Athens, Greece
Sophia Antimisiaris, Professor, Department of Pharmacy, University of Patras, Greece
Annette Bauer-Brandl, Professor, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Denmark
Dimitrios Fatouros, Professor, Department of Pharmacy, Aristotle University of Thessaloniki, Greece
Brendan Griffin, Professor, School of Pharmacy, University College Cork, Ireland

Understanding and evaluating the performance of orally administered medicinal products in the upper and in the lower gastrointestinal lumen

English

Understanding and evaluating the performance of orally administered medicinal products in the upper and in the lower gastrointestinal lumen

The present thesis had three main objectives:
1. To evaluate the clinical efficacy of an antacid chewable tablet,
2. To evaluate the Biorelevant Gastrointestinal (BioGIT) system in screening for differences
in early intestine under normal and reduced gastric acid secretions,
3. To evaluate the usefulness of optimized human fecal material in simulating the bacterial
degradation of sulfoxides in the lower intestine.
For the evaluation of the clinical efficacy of the antacid chewable tablets AA [calcium
carbonate (0.500 g/tab) and magnesium oxide (0.250 g/tab), ΑΑ tablets], twelve healthy male
adults were intubated with a nasogastric feeding tube and gastric contents were aspirated
from the antrum of the stomach for 60 min before and 60 min after the administration of two
AA tablets. The pH was measured upon aspiration. The individual pH values ranged from 1.2
to 2.7 before the administration of AA tablets. After the administration of two AA tablets
gastric pH increased within 5 min for all volunteers with values ranging from 5.8 to 9.1. The
time needed for the pH to return to baseline values was quite variable among the volunteers.
Administration of two AA tablets significantly increases the fasting gastric pH of healthy young
adults to values higher than the baseline value for a period of at least 45 min.
For the evaluation of BioGIT system in screening for differences in early exposure, the impact
of dose and/or formulation on early exposure after administration of disintegrating
immediate release or enabling drug products of lipophilic APIs with a glass of water in the
fasted state was firstly assessed. Data from BioGIT experiments using three model compounds
(Compound A, Compound E and fenofibrate), formulated at various doses and/or dosage
forms were evaluated based on plasma data. Mean BioGIT AUC0–50min values were useful for
evaluating the impact of dose and/or formulation on early exposure after administration of viii products of lipophilic active pharmaceutical ingredients (APIs) to healthy fasted adults with a
glass of water. The ratios of AUC values of the data collected during this study and of
previously collected data were calculated for the BioGIT and the respective plasma data. The
ratios were logarithmically transformed and included to a previously established correlation
between log-transformed BioGIT AUC0-50min ratios and log-transformed plasma AUC0-60min in
order to strengthen the observed relationship. This implementation of the data improved the
characteristics of the correlation and further confirmed the usefulness of BioGIT as a screening
tool for assessing the impact of dose and/or formulation on early exposure. Potential
limitations of the BioGIT system in evaluating the effect of dose or formulation in the early
exposure in the fasted state were also investigated using four case studies. BioGIT data can
be misleading when data are highly variable, when the dose is not administered with a glass
of water and/or when aqueous drug solutions are used. Finally, the rapid dissolution of
nanocrystals after administration of low solubility weak bases requires adjustment of the pH
in the gastric compartment of BioGIT to slightly higher pH values. These limitations identified
for BioGIT system may also apply to other relevant in vitro methodologies for which relevant
data are still lacking. Lastly, the usefulness of BioGIT in evaluating the impact of reduced
gastric acid secretions on intraluminal concentrations was assessed using three model low
solubility weakly basic compounds (indinavir sulfate, atazanavir sulfate and ritovanir). BioGIT
could be effectively used as a screening tool for predicting possible effect of reduced gastric
acid secretions on intraluminal concentrations of weakly basic compounds. Special caution
should be given to APIs formulated as salts, as the effect of possible differences between
human and simulated media composition may lead to under- (or maybe over-) estimation of
the magnitude of the effect.
For the evaluation of the usefulness of optimized human fecal material in simulating the
bacterial degradation of sulfinpyrazone and sulindac in the lower intestine, ex vivo
degradation experiments in Simulated Colonic Bacteria (SCoB) were performed under
anaerobic conditions and the data were evaluated against published in vivo data. The
degradation of both sulfoxides in SCoB was substantial. Sulindac, sulindac sulfide and sulindac
sulfone data in SCoB indicate complete degradation of sulindac to sulindac sulfide. Sulindac
data indicate that colonic bacteria lead only to reduction of the sulfoxide group of those drugs,
with no oxidative product being detected. SCoB material can be useful as a screening tool in
simulating sulforeductase activity in the lower intestine at early stages of drug development
process.

Science

antacids, BioGIT, hypochlorydria, simulated colonic bacteria, immediate release drug products

Yes

4

Yes

178

173

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