Physiologically based pharmacokinetics of a new penem, SUN5555, for evaluation of in vivo efficacy.

SUN5555, (5R,6S)-6-[(R)-1-hydroxyethyl]-7-oxo-3-[(R)-2- tetrahydrofuryl]-4-thia-1-azabicyclo-[3.2.0]-hept-2-ene-carboxylic acid, is a newly developed and orally effective penem with a broad antibacterial spectrum. SUN5555 was degraded in rat tissue homogenates and serum, and its degradations in the kidney and lung homogenates were significantly inhibited by cilastatin, an inhibitor of dehydropeptidase I. The pulmonary extraction was evaluated to be 0.033 by comparing the AUCs resulting from iv and intra-arterial administration of 10 mg/kg. From the arterial-to-venous concentration differences under steady state conditions in rats, extraction ratios of SUN5555 across the kidney, hind leg, gut, and liver were determined to be 0.333, 0.104, 0.071 and 0.053, respectively, whereas no appreciable extraction across the brain was observed. Therefore, organ clearances of SUN5555 are limited by the product of plasma unbound fraction and organ intrinsic clearances in various tissues. Using a physiologically based pharmacokinetic model, unbound concentrations of SUN5555 in the tissue interstitial fluids, which are the measure of in vivo antibacterial efficacy, were estimated to be almost identical with, or higher than, those in plasma in rats. Similarly, serum concentration-time profiles of SUN5555 after iv administration in other animal species were predicted and found to be in good agreement with the observed data in dogs. A preliminary prediction of the pharmacokinetics of SUN5555 in a human subject was also attempted by animal scale-up technique.