Advantages of the refined developability classification system in early discovery

Rat pharmacokinetic studies are commonly utilized in early discovery to support absorption, distribution, metabolism, and excretion optimization of active pharmaceutical ingredients (APIs). The aim of this work was to compare exposures from fit-for-purpose oral suspension and solution formulations in rats to guidance provided by the refined Developability Classification System (rDCS) with respect to identifying potential limits to oral absorption, formulation strategy selection, and to optimize oral bioavailability (BA). This investigation utilized six diverse APIs covering a large range of biorelevant solubility, metabolic stability, and oral BA in rats. While results for our model compounds acetaminophen, voriconazole, fedratinib, lemborexant, and istradefylline indicated oral BA in rats was limited by first-pass metabolism, only the results for voxelotor indicated an oral absorption limitation by intestinal dissolution/solubility. The in vivo studies highlighted challenges and limitations often encountered in early discovery. The rDCS analysis provided a more differentiated developability risk assessment associated with oral solid dosage form development by incorporating compound-specific physicochemical attributes and human physiology without the need of preclinical data. The rDCS results were shown to align well with the clinical/marketed formulation strategies for the investigated APIs.