Viscosity-mediated negative food effect on oral absorption of poorly-permeable drugs with an absorption window in the proximal intestine: In vitro experimental simulation and computational verification

Cvijić, Sandra; Parojčić, Jelena; Langguth, Peter

doi:10.1016/j.ejps.2014.04.008

Cited by 64 publications

(39 citation statements)

References 63 publications

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“…In humans, the fed-state GI lumen may have a dynamic, viscous, partially digested meal that can disrupt the supersaturated solubility of drugs perhaps by triggering nucleation and/or particle growth which in turn reduces the extent of FE (29). Consistent with this scenario, Shono et al (30) found the biorelevant dissolution overpredicted the FE risk for celecoxib by 7-fold, while the human FE ratio was only 1.3.…”

Section: In Vitro-in Vivo Relationship (Ivivr)supporting

confidence: 57%

“…5). BMS-F and BMS-H are examples of such compounds where it is generally thought that the physical entrapment of the drug in the viscous, post-prandial GI fluid milieu leads to unavailability of free drug for absorption through the paracellular junctions (29). Kawai et al (37) reported that hydrophilic drugs that dissolve rapidly are more likely to be limited by their permeation rates due to physical interaction with food components in the fed state.…”

Section: Case Studies On Fe Mechanismsmentioning

confidence: 99%

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Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models

Mathias

Yang

Vig

et al. 2015

AAPS J

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Abstract. In vitro and in vivo experimental models are frequently used to assess a new chemical entity's (NCE) biopharmaceutical performance risk for food effect (FE) in humans. Their ability to predict human FE hinges on replicating key features of clinical FE studies and building an in vitro-in vivo relationship (IVIVR). In this study, 22 compounds that span a wide range of physicochemical properties, Biopharmaceutics Classification System (BCS) classes, and food sensitivity were evaluated for biorelevant dissolution in fasted-and fed-state intestinal media and the dog fed/fasted-state pharmacokinetic model. Using the area under the curve (AUC) as a performance measure, the ratio of the fed-to-fasted AUC (FE ratio) was used to correlate each experimental model to FE ratio in humans. A linear correlation was observed for the in vitro dissolution-human IVIVR (R 2 =0.66, % mean square error 20.7%). Similarly, the dog FE ratio correlated linearly with the FE ratio in humans (R 2 =0.74, % mean square error 16.25%) for 15 compounds. Data points near the correlation line indicate dissolution-driven mechanism for food effect, while deviations from the correlation line shed light on unique mechanisms that can come into play such as GI physiology or unusual physicochemical properties. In summary, fed/fasted dissolution studies and dog PK studies show a reasonable correlation to human FE, hence are useful tools to flag high-risk NCEs entering clinical development. Combining kinetic dissolution, dog FE model and in silico modeling one can study FE mechanism and formulation strategies to mitigate the FE risk.KEY WORDS: biorelevant dissolution; dog food effect model; food effect; in vitro-in vivo relationship.

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Section: In Vitro-in Vivo Relationship (Ivivr)supporting

confidence: 57%

Section: Case Studies On Fe Mechanismsmentioning

confidence: 99%

Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models

Mathias

Yang

Vig

et al. 2015

AAPS J

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“…The third important change is the composition of the gastrointestinal fluids. In the fed-state, the fluids exhibit higher buffer capacities, higher osmolality and higher concentrations of short-chain fatty acids and bile salts [142]. Any of these changes may affect the absorption of drugs from the GI-tract.…”

Section: Foodmentioning

confidence: 99%

Variability in bioavailability of small molecular tyrosine kinase inhibitors

Herbrink

Nuijen

Schellens

et al. 2015

Cancer Treatment Reviews

111

104

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“…Dissolution and disintegration for drugs with limited permeability such as atenolol, metformin hydrochloride, furosemide and metoprolol tartrate was decreased significantly in viscous medium (Cvijic et al, 2014). Using xanthan gum or guar gum to increase the viscosity of dissolution media causes a reduction in benzoic acid dissolution (Sarisuta and Parrott, 1982).…”

Section: Administration With Thickenersmentioning

confidence: 99%

Oral medication dose form alteration: patient factors and the effect of adding thickened fluids

Radhakrishnan¹

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Solid oral dosage forms such as tablets and capsules are often crushed and mixed with foods or fluids to aid drug delivery for those who cannot or prefer not to swallow them whole. Some people have a physiological problem limiting swallowing (dysphagia), and their fluids are thickened to ensure safe swallowing; these thickened fluids are also used to deliver crushed medication in replacement of water. This thesis explores the issues surrounding the swallowing of whole tablets and capsules, their modification by crushing and the influence of coadministration with thickened fluids on absorption pharmacokinetics. The literature review (Chapter 1) examines the physiology and pathophysiology of swallowing and considers the particular issues surrounding swallowing tablets and capsules. It also explores the possible consequences of crushing the medications and mixing the powder with vehicles such as jam, honey, yoghurt and thickened water.This thesis contains two sections. In Section A (Chapter 2), the potential influence of psychological issues, oral sensation, sensory effect and motor ability of an individual on swallowing pills was investigated. It is hypothesised that swallowing tablets and capsules will be an issue in people with a memory of gagging on food and medication, strong gag reflex, heightened taste sensation, or who tend to chew their food for extended periods.Volunteers (153) completed a written survey and one-on-one assessments. Psychological issues were addressed by questions on memory of choking incidents on food or medication, and regularity of medication use. Sensory effects were assessed by measuring the person's gag reflex, taste receptor density, size of the mouth (mallampati classification), and on food neophobia. Motor effects were assessed as efficiency in chewing a jelly snake. Finally, the volunteers were observed swallowing a capsule and the quantity of water used, and head position was recorded.In the survey, 33% of the population reported that they have had trouble swallowing medication.These people were more likely to have choked on medication in the past, have a smaller mouth cavity, and a medium or high taste receptor density. There was no relationship between trouble swallowing medication and gag reflex, food neophobia, chewing efficiency, quantity of water used to swallow, and head position.In Section B (Chapters 3, 4, and 5), the effect of crushing medication and mixing with water thickened with a commercial thickening agent on absorption pharmacokinetics was studied.ii Paracetamol tablets were used as the model drug, and saliva samples were used to measure the PK profile. Chapter 3 assessed the inter-and intra-individual variability as the coefficient of variation of paracetamol in saliva. Volunteers took whole tablets of paracetamol (2 x 500 mg) on two different days separated by a week. Saliva production was stimulated using citric acid and paracetamol levels in the saliva were measured using high-performance liquid chromatography. Non-compartmental pharmacokinetic analy...

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Viscosity-mediated negative food effect on oral absorption of poorly-permeable drugs with an absorption window in the proximal intestine: In vitro experimental simulation and computational verification

Cited by 64 publications

References 63 publications

Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models

Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models

Variability in bioavailability of small molecular tyrosine kinase inhibitors

Oral medication dose form alteration: patient factors and the effect of adding thickened fluids

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