Screening for Differences in Early Exposure in the Fasted State with in Vitro Methodologies can be Challenging: Experience with the BioGIT System.

The Biorelevant Gastrointestinal Transfer (BioGIT) system is a useful screening tool for assessing the impact of dose and/or formulation on early exposure after administration of immediate release or enabling drug products with a glass of water in the fasted state. The objective of this study was to investigate potential limitations. BioGIT experiments were performed with five low solubility active pharmaceutical ingredients with weakly alkaline characteristics: mebendazole (tablet and chewable tablet), Compound E (aqueous solutions, three doses), pazopanib-HCl (Votrient™ tablet, crushed Votrient™ tablet and aqueous suspension), Compound B-diHCl (hard gelatin capsule, three doses) and Compound C (hard gelatin capsule containing nanosized drug and hard gelatin capsule containing micronized drug). For all formulation or dose comparisons the ratio of mean BioGIT AUC0-50 min values was not predictive of the ratio of mean plasma AUC0-60 min values which became available after completion of BioGIT experiments. BioGIT experimental conditions have not been designed to simulate the gastrointestinal drug transfer process after administration of chewable tablets or aqueous solutions, therefore, BioGIT may not be useful for the assessment of intraluminal performance early after administration of such drug products. Also, based on this study, BioGIT may not be useful in investigating the impact of dose and/or formulation on early exposure when the dose is not administered with a glass of water to fasted healthy individuals or when BioGIT data are highly variable. Finally, the rapid dissolution of nanocrystals after administration of low solubility weak bases may require adjustment of the pH in the gastric compartment of BioGIT to slightly higher pH values. Limitations identified in this study for the BioGIT system may be also relevant to other in vitro systems proposed for similar evaluations.

Usefulness of the BioGIT system in screening for differences in early exposure in the fasted state on an a priori basis.

The objective of the present study was to confirm the usefulness of BioGIT data in the evaluation of the impact of dose and/or formulation on early exposure after oral administration of immediate release or enabling products of low solubility active pharmaceutical ingredients (APIs) with a glass of water in the fasted state. BioGIT experiments were performed with four APIs: Compound Α (tablet, three dose levels), Compound E (capsule PiC1, capsule PiC2 and tablet), fenofibrate (Lipidil® capsule and Lipidil 145 ONE® tablet) and Compound F (HP-ß-CD aqueous solution and tablet). Based on mean plasma AUC0-60min values which became available after completion of the BioGIT experiments, mean BioGIT AUC0-50min values were useful for the evaluation of the impact of dose and/or formulation on early exposure. The log-transformed ratios of mean BioGIT AUC0-50min values for two doses and/or two formulations estimated in this study and in a recent study for two diclofenac potassium products (Cataflam® tablet and Voltfast® sachet, same dose) vs. the corresponding log-transformed ratios of mean plasma AUC0-60min values (n = 7 pairs of ratios), were included in a previously established correlation between log-transformed ratios of mean BioGIT AUC0-50min values and log-transformed ratios of plasma AUC0-60min values (n = 9 pairs of ratios). The correlation between log-transformed plasma AUC0-60min ratios vs. log-transformed BioGIT AUC0-50min ratios was confirmed (n = 16 pairs of ratios, R = 0.90). Compared with the previously established correlation the statistical characteristics were improved. Based on this study, the BioGIT system could be useful as a screening tool for assessing the impact of dose and/or formulation differences on early exposure, after administration of immediate release or enabling drug products of low solubility APIs with a glass of water in the fasted state, on an a priori basis.