ORAL ABSORPTION OF CGS-20625, AN INSOLUBLE DRUG, IN DOGS AND MAN

Oral bioavailability of highly water-insoluble drugs is often quite li mited and variable, requiring the development of improved formulations . Animal models are an essential aspect of the design and testing of s uch formulations designed to improve absorption in man The present rep ort compares the absorption of CGS-20625, an insoluble drug, in dog an d man after oral administration of the drug as a powder, a solid dispe rsion capsule, and after gastric and duodenal administration in PEG 40 0 solution. CGS-20625 powder (20 mg) given orally exhibited slow, dela yed absorption in both dog and man, with a C-max of 0.26 +/- 0.07 mu g /ml at T-max of 3 hr in dog, and 0.01 +/- 0.004 mu g/ml at 2 hr in man . Administration of CGS-20625 in PEG 400 solution improved absorption in dog and mart, with a C-max of 1.2 +/- 0.10 mu g/ml at T-max of 0.25 hr in dog, and a C-max of 0.10 +/- 0.04 mu g/ ml at 0.5 hr in man. T- max after administration of the hard gelatin capsule formulation was 0 .9 and 1.0 hr in dog and man, with C-max of 0.89 +/- 0.16 and 0.052 +/ - 0.014 mu g/ml, respectively. Absolute bioavailability of CGS-20625 p owder in the dog was 0.67 +/- 0.21, whereas the bioavailabilities of t he powder and the capsule relative to the PEG 400 solution were 0.84 a nd 1.1, respectively, in dog, and 0.41 and 0.85 respectively, in man. No significant benefits of duodenal administration were observed. Plas ma levels were approximately 10-fold greater and oral clearance was ap proximately 5-fold less in the dog than in man. Furthermore, pharmacok inetic data were less variable and relative bioavailability was greate r in dogs than in humans. Physiological factors in the gastrointestina l tract or greater first-pass metabolism in man may account for these species differences. The relative rate and extent of CGS-20625 absorpt ion were similar between dog and man, in the order of powder < capsule < PEG 400 solution. In addition, in vivo absorption rates in both spe cies reflect in vitro dissolution differences between the powder and t he capsule. These data strongly support the use of the clog as a model for developing improved formulations of CGS-20625. Further investigat ion of the dog as a model to evaluate insoluble drug absorption is war ranted.