Drug Disposition Classification Systems in Discovery and Development: A Comparative Review of the BDDCS, ECCS and ECCCS Concepts.

BDDCS, ECCS and ECCCS are compound disposition classification concepts that aim to streamline, de-risk and speed-up drug development. Although all three systems have the same purpose and are based on classifying drugs into four main categories, they have different backgrounds and contrast in their criteria. Here the details, differences and most important applications of the three systems are reviewed with particular emphasis of their roles for drug discovery and development.

In vitro blood distribution and plasma protein binding of the iron chelator deferasirox (ICL670) and its iron complex Fe-[ICL670]2 for rat, marmoset, rabbit, mouse, dog, and human.

Deferasirox (Exjade, ICL670) is an orally active iron chelator. Two molecules of deferasirox can form a complex with ferric iron (Fe-[ICL670]2) that can be excreted, reducing body iron overload. The blood binding parameters across species and the interaction with human serum albumin were analyzed for deferasirox and its iron complex. Both molecules were very highly bound to plasma proteins in all the tested species with unbound fractions in plasma in the range of 0.4 to 1.8% and 0.2 to 1.2% for deferasirox and Fe-[ICL670]2, respectively; binding of the iron complex was either similar or higher in all the species. The high plasma protein binding was in line with a distribution mainly into the plasma fraction of blood; the fraction in plasma was around 100% for Fe-[ICL670]2 in all the species and 65 to 95% for deferasirox depending on the species. Investigations with isolated proteins pointed to serum albumin as the principal binding protein for deferasirox and its iron complex in human plasma. Competition binding experiments indicated that deferasirox at high concentrations displaced markers from the two main drug binding sites of human albumin, whereas Fe-[ICL670]2 displaced only warfarin. In the context of the pharmacokinetic properties of deferasirox and Fe-[ICL670]2, the data indicate the importance of plasma protein binding for their disposition and support a comparison of the pharmacokinetics of deferasirox and its iron complex across species. The low likelihood of clinically relevant drug displacement by deferasirox in plasma is discussed.

The outstanding metabolic stability of a 14C-labeled beta-nonapeptide in rats--in vitro and in vivo pharmacokinetic studies.

IN VITRO STUDIES: In CaCo-2 cell monolayers the beta-nonapeptide H(beta-HAla-beta-HLys-beta-HPhe)(3)-OH.4HCl (1), (14)C-labeled on both C atoms of the CH(2)-CO moiety of the central beta-HPhe residue, showed a low intrinsic permeability (<1%) and is subject to a prominent efflux system. The beta-peptide (1) binds to human and rat plasma protein in vitro independent of the concentration of 1 and of the species (30-36% bound fraction at 50, 500, and 5000 ng/ml), and has only low affinity for the corresponding blood cells (less than 5% of compound 1 in blood cells). IN VIVO STUDIES: The in vivo pharmacokinetic characteristics after i.v. administration of 5 mg/kg (to male rats and to bile-duct-operated rats) were: (i) negligible in vivo biotransformation of 1 (in urine, plasma and feces unchanged 1 represented virtually the only compound-related molecule); (ii) rapid initial decline (0-8 h post dose) of levels of compound 1 in blood and plasma followed by a slower decline (8-96 h post dose); (iii) in non-operated animals after 96 h only 38% of the dose was excreted and after 168 h 49% of the dose was found remaining in the carcass; elimination through the intestine wall represented the major elimination pathway in non-operated animals while in bile-duct-cannulated animals biliary excretion was not found to contribute substantially to elimination (iv) quantitative whole-body autoradioluminography (QWBAL) investigations revealed that the kidney was by far the most important target organ of distribution; other tissues with high concentrations of compound-related radioactivity were cartilage, lymph nodes, and liver, whereas lowest levels were found in white fat and in the brain. After p.o. administration (10 mg/kg) negligible radioactivity was observed in the systemic circulation, indicating negligible absorption; essentially the entire oral dose was recovered unchanged in feces collected over a period of 96 h.