Evaluation of Food Effect on the Absorption of Clarithromycin using Physiological Modeling
جيوسي, رند خليل عبداللطيف
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Background: Food may affect the oral absorption of drugs by inducing physiological changes in the gastrointestinal physiology, such as: gastrointestinal pH, gastric residence time, bile salt secretion and drug metabolism. Purpose: The aim of the present study was to investigate the influence of food on the oral absorption of Clarithromycin by evaluating the effect of media parameters such as; pH, bile secretions and food composition, on the release of the drug from immediate release tablet, using in vitro and in silico assessments Method: The solubility, disintegration and dissolution profiles of Clarithromycin 500 mg immediate release tablets in compendial media with/without the addition of homogenized FDA meal as well as in biorelevant simulated intestinal media mimicking fasting and fed conditions were determined. These in vitro data were input to GastroPlusTM to make computational simulation in order to anticipate the effect of food on Clarithromycin absorption profiles under fasted and fed states. In vivo plasma concentration curves were used for compartmental modeling of pharmacokinetic data. Level A in vitro – in vivo linear correlations were established using mechanistic absorption modeling based deconvolution approach. Gastroplus™ was used for developing a physiological absorption model for Clarithromycin, which is capable of predicting the in vivo performance Results: Media pH has a profound effect on drug solubility, tablet disintegration and drug release. Clarithromycin has lower solubility in the biologically biorelevant media compared to other media, due to complex formation with bile salts. Clarithromycin tablets exhibited prolonged disintegration times and reduced dissolution rates in the presence of the standard FDA meal. The simulation model predicted no significant food effect on the oral bioavailability of Clarithromycin. The developed IVIVC model considered SIF, acetate, and FaSSIF buffer media to be the most relevant from the physiological standpoint. Conclusion: the intake of standard FDA meal with Clarithromycin may have no significant effect on oral bioavailability of Clarithromycin from immediate release tablets. This may suggest that the dissolution conditions recommended by ICH are sufficient to demonstrate interchangeability between generic and brand Clarithromycin, a class II drug, especially during the developmental phase of the generic product.