The BioGIT System: a Valuable In Vitro Tool to Assess the Impact of Dose and Formulation on Early Exposure to Low Solubility Drugs After Oral Administration

Q3 · MEDICINE

Article

Author: Kourentas, Alexandros ; Butler, James ; Barmpatsalou, Vicky ; Rosenberg, Joerg ; Ouwerkerk, Neils ; Symillides, Mira ; Vertzoni, Maria ; Tajiri, Tomokazu ; Tannergren, Christer ; Augustijns, Patrick ; Reppas, Christos ; Holm, Rene ; Beato, Stefania

The purpose of this study was to evaluate the usefulness of the in vitro biorelevant gastrointestinal transfer (BioGIT) system in assessing the impact of dose and formulation on early exposure by comparing in vitro data with previously collected human plasma data of low solubility active pharmaceutical ingredients. Eight model active pharmaceutical ingredients were tested; Lu 35-138C (salt of weak base in a HP-beta-CD solution, three doses), fenofibrate (solid dispersion, tablet, two doses), AZD2207 EQ (salt of weak base, capsule, three doses), posaconazole (Noxafil® suspension, two doses), SB705498 (weak base, tablets vs. capsules), cyclosporine A (Sandimmun® vs. Sandimmun® Neoral), nifedipine (Adalat® capsule vs. Macorel® tablet), and itraconazole (Sporanox® capsule vs. Sporanox® solution). AUC_0-0.75h values were calculated from the apparent concentration versus time data in the duodenal compartment of the BioGIT system. Differences in AUC_0-0.75h values were evaluated versus differences in AUC_0-1h and in AUC_0-2h values calculated from previously collected plasma data in healthy adults. Ratios of mean AUC_0-0.75h, mean AUC_0-1h, and mean AUC_0-2h values were estimated using the lowest dose or the formulation with the lower AUC_0-0.75h value as denominator. The BioGIT system qualitatively identified the impact of dose and of formulation on early exposure in all cases. Log-transformed mean BioGIT AUC_0-0.75h ratios correlated significantly with log-transformed mean plasma AUC_0-1h ratios. Based on this correlation, BioGIT AUC_0-0.75h ratios between 0.3 and 10 directly reflect corresponding plasma AUC_0-1h ratios. BioGIT system is a valuable tool for the assessment of the impact of dose and formulation on early exposure to low solubility drugs.

01 Nov 2016·Journal of Pharmaceutical SciencesQ3 · MEDICINE

Biopharmaceutic Profiling of Salts to Improve Absorption of Poorly Soluble Basic Drugs

Q3 · MEDICINE

Article

Author: Karlsson, Eva ; Tannergren, Christer ; Sigfridsson, Kalle ; Ku, Angela ; Polentarutti, Britta ; Lindfors, Lennart ; Carlert, Sara

AZD1175 and AZD2207 are 2 highly lipophilic compounds with a significant risk of not achieving therapeutic plasma concentrations due to solubility-limited absorption. The compounds have the same molecular weight and minimal structural differences. The aim of the present work was to investigate whether salts could be applied to improve the intestinal absorption, and the subsequent in vivo exposure. Drug solubilities, dissolution rates, and degree of supersaturation and precipitation were determined in biorelevant media. Dog studies were performed, in the absence and presence of a precipitation inhibitor (hydroxypropyl methylcellulose). Finally, a human phase I study was performed. For AZD1175, there was a good agreement between dissolution rates, in vivo exposure in dog, and the obtained exposure in human with the selected hemi-1,5-naphthalenedisulfonate of the compound. For AZD2207, the picture was more complex. The same counter ion was selected for the study in man. In addition, the chloride salt of AZD2207 showed promising data in the presence of a precipitation inhibitor in vitro and in dog that, however, could not be repeated in man. The differences in observations between the 2 compounds could be attributed to the difference in solubility and to the degree of supersaturation in the gastric environment rather than in the intestine.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Phase 2	-	AstraZeneca PLC	-
Diabetes Mellitus, Type 2	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Obesity	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Obesity	Phase 2	-	AstraZeneca PLC	-

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