Effects of ranitidine (antacid), food, and formulation on the pharmacokinetics of fostamatinib: results from five phase I clinical studies.

PURPOSE: Fostamatinib is an orally dosed phosphate prodrug that is cleaved by intestinal alkaline phosphatase to the active metabolite R406. Clinical studies were performed to assess the effect of food and ranitidine on exposure, to support in vitro-in vivo relationships (IVIVR) understanding and formulation transitions and to investigate absolute oral bioavailability. METHODS: A series of in vitro dissolution and clinical pharmacokinetic studies were performed to support the design and introduction of a new formulation, understand the impact of changes in in vitro dissolution on in vivo performance for two fostamatinib formulations, to characterize the effects of food and ranitidine on exposure, and determine the absolute oral bioavailability. RESULTS: The in vivo performance of fostamatinib was generally insensitive to changes in in vitro dissolution performance, although marked slowing of the dissolution rate did impact exposures. Food and ranitidine had minor effects on R406 exposure that were not considered clinically relevant. The absolute oral bioavailability of fostamatinib was 54.6 %. CONCLUSIONS: The absolute oral bioavailability of fostamatinib was ~55 %. Food and ranitidine had minor effects on R406 exposure. An in vitro dissolution versus clinical performance relationship was determined that supported formulation transitions.

Spore exines increase vitamin D clinical bioavailability by mucoadhesion and bile triggered release.

Sporopollenin exine capsules (SpECs) are microcapsules derived from the outer shells (exines) of plant spore and pollen grains. This work reports the first clinical study on healthy volunteers to show enhanced bioavailability of vitamin D encapsulated in SpECs from Lycopodium clavatum L. spore grains vs vitamin D alone, and the first evidence (in vitro, ex vivo and in vivo) of mechanisms to account for the enhancement and release of the active in the small intestine. Evidence for mucoadhesion of the SpECs contributing to the mechanism of the enhancement is based on: (i) release profile over time of vitamin D in a double blind cross-over human study showing significant release in the small intestine; (ii) in vivo particle counting data in rat showing preferred retention of SpECs vs synthetic beads; (iii) ex vivo99mTc labelling and counting data using rat small intestine sections showing preferred retention of SpECs vs synthetic beads; (iv) in vitro mucoadhesion data. Triggered release by bile in the small intestine was shown in vitro using solid state NMR and HPLC.

Structure-interaction relationships between the bile acid GCA and pharmaceuticals using multivariate data analysis and capillary electrophoresis.

Capillary electrophoresis (CE) has been used in an interaction study of 66 pharmaceutical compounds with the bile acid glycocholate (GCA). The developed method proved to have a high precision in its ability to determine the mobility of drugs in buffer and buffer bile acids solutions. The relationship between solute structure and interaction with GCA was studied using two-dimensional descriptors with the in-house software SELMA and a three-dimensional model (quantum mechanical descriptors) in combination with the experimental CE-interaction data. The multivariate analysis method used was projection to latent structures by means of partial least squares (PLS). Two selections of training and test set were used for evaluation of a two-class model on interaction data. In the first selection all observations were used for training set, for example, creating a model, and re-predicting the observations on the model. A successful prediction on 85% of the drugs was observed using this model. The second selection used the 21 first tested compounds in the training set, where 78% of the compounds were correctly predicted using the two-dimensional model (SELMA) on the remaining 45 compounds and, respectively, 82% using the three-dimensional (quantum mechanical) model. Analysis of the impact of the descriptors showed that descriptors relating to hydrophobicity have a large positive effect on the interaction. Descriptors relating to polar properties have a pronounced negative effect on the interaction of drugs with bile acids.

Application and validation of an advanced gastrointestinal in vitro model for the evaluation of drug product performance in pharmaceutical development.

Methods to understand and predict the oral bioavailability of drug products are a prioritized research area within the pharmaceutical industry. Models to predict oral bioavailability have the potential to reduce risk, time, and cost in development as well as decrease the need for animal studies. The TNO intestinal model (TIM-1) is an advanced dissolution model deployed by AstraZeneca since 2008. This article presents a systematic evaluation of TIM-1 against in vivo data. The relative performance of compounds and formulations tested in TIM-1 and in vivo was compared both by a qualitative analysis and a linear regression analysis of relative exposure measures between test and reference formulations in TIM-1 and in vivo. The TIM-1 correctly predicted in vivo rank order in 84% and 79% of cases for AUC and Cmax , respectively, when using the 3-h time point. There was only one case for Cmax in which TIM-1 did not predict an in vivo difference. The correlation coefficient (R(2) ) between relative (test vs. reference formulations) fraction available in TIM-1 after 3 h and AUC was 0.78. Thus, this study suggests that the TIM-1 system can be used to assess the risk for significant differences in exposure between formulations and compound modifications.