Scintigraphic Study to Investigate the Effect of Food on a HPMC Modified Release Formulation of UK-294,315

• Published in: Journal of pharmaceutical sciences 2009-04, Vol.98 (4), p.1568-1576
• Main Authors: Davis, J., Burton, J., Connor, A.L., Macrae, R., Wilding, I.R.
• Format: Article
• Language: English
• Subjects: Adrenergic alpha-1 Receptor Antagonists; Adult; Azepines - blood; Azepines - chemistry; Azepines - pharmacokinetics; Biological and medical sciences; Biological Availability; Delayed-Action Preparations; Drug Carriers - chemistry; Fasting; food effects; Food-Drug Interactions; Gastrointestinal Tract - diagnostic imaging; Gastrointestinal Transit - physiology; General pharmacology; Humans; Hypromellose Derivatives; Male; Medical sciences; Methylcellulose - analogs & derivatives; Methylcellulose - chemistry; Middle Aged; modified release; Pharmaceutical technology. Pharmaceutical industry; pharmacokinetics; Pharmacology. Drug treatments; Postprandial Period; Quinolines - blood; Quinolines - chemistry; Quinolines - pharmacokinetics; Radioisotopes; Radionuclide Imaging; Samarium; scintigraphy; UK-294; UK-294,315
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.21507

The objective of the study was to use the combined approach of gamma scintigraphy and pharmacokinetics, in order to understand the mechanisms explaining the pharmacokinetic differences observed for a modified release (MR) formulation, when administered either in the fed or fasted state. Ten healthy subjects were recruited into a randomized three period single dose study, each subject receiving UK-294,315 40mg IR (fasted), 100mg MR (fasted) or 100mg MR (after a high fat meal). Cmax values were markedly higher for the MR tablet in the fed state versus fasted and mean residence time was about 3h longer for fasted versus fed; there was little difference in apparent oral clearance. In the fasted state, average gastric emptying of the intact tablet occurred at 1.2h postdose, with gastric emptying of intact tablet observed in all subjects. In the fed state, rapid disintegration of the MR tablet was observed by scintigraphy, with 7/9 subjects showing complete disintegration in the stomach. Complete disintegration occurred 10.1h postdose in the fasted state versus 5.9h after a high fat meal. The study showed that in the fed state, the MR tablet eroded more rapidly than in the fasted state, leading to an overall increase in the rate of absorption.