Dimitris Papoutsakis

Selection of oral bioavailability enhancing formulations during drug discovery

The objective of this paper was to identify oral bioavailability enhancing approaches for a poorly water-soluble research compound during drug discovery stages using minimal amounts of material. LCQ789 is a pBCS (preclinical BCS) Class II compound with extremely low aqueous solubility (<1 µg/mL) and high permeability, therefore, resulting in very low oral bioavailability in preclinical species (rats and dogs). A number of solubility and/or dissolution enhancing approaches including particle size reduction, solid dispersions, lipid-based formulations and co-crystals, were considered in order to improve the compound’s oral bioavailability. High-Throughput Screening (HTS) and in silico modeling (GastroPlus™) were utilized to minimize the compound consumption in early discovery stages. In vivo evaluation of selected physical form and formulation strategies was performed in rats and dogs. Amongst the formulation strategies, optimized solid dispersion and lipid-based formulation provided significant improvement in drug dissolution rate and hence, oral bioavailability. In addition, a significant impact of physical form on oral bioavailability of LCQ789 was observed. In conclusion, a thorough understanding of not only the formulation technique but also the physical form of research compounds is critical to ensure physical stability, successful pharmacokinetic (PK) profiling and early developability risk assessment.

Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features

Racial/ethnic disparities in breast cancer mortality continue to widen but genomic studies rarely interrogate breast cancer in diverse populations. Through genome, exome, and RNA sequencing, we examined the molecular features of breast cancers using 194 patients from Nigeria and 1037 patients from The Cancer Genome Atlas (TCGA). Relative to Black and White cohorts in TCGA, Nigerian HR + /HER2 − tumors are characterized by increased homologous recombination deficiency signature, pervasive TP53 mutations, and greater structural variation—indicating aggressive biology. GATA3 mutations are also more frequent in Nigerians regardless of subtype. Higher proportions of APOBEC-mediated substitutions strongly associate with PIK3CA and CDH1 mutations, which are underrepresented in Nigerians and Blacks. PLK2, KDM6A, and B2M are also identified as previously unreported significantly mutated genes in breast cancer. This dataset provides novel insights into potential molecular mechanisms underlying outcome disparities and lay a foundation for deployment of precision therapeutics in underserved populations.Research on racial and ethnic influence on breast cancer mortality is stymied by a lack of genomic studies in diverse populations. Here, the authors genomically interrogate 194 Nigerian breast cancers, unveiling molecular features that could explain the high mortality rate from breast cancer in an indigenous African population.