Sonya C. Tate1, Yu-Hua Hui2, David Barda2, James Henry2, Jian Du2
1Eli Lilly and Company, Windlesham, United Kingdom; 2Eli Lilly and Company, Indianapolis, IN, USA
Objectives: During early drug discovery, characterising the quantitative pharmacology of early tool compounds is an important component of candidate design and selection. By understanding the desired extent and duration of target engagement, project teams can better select the pharmacokinetic / pharmacodynamic (PK/PD) properties to optimise, resulting in clinical candidates with a higher probability of success. Furthermore, once the pharmacology of a tool compound has been evaluated, the behaviour of each emerging candidate of interest need only be confirmed with streamlined, targeted study designs. The objective of this work was to quantify the extent and duration of selective Aurora A inhibition required for tumour shrinkage using a tool compound (Compound X), and to translate these findings to emerging Aurora A inhibitors of interest, of which LY3295668 was ultimately selected for progression to the clinic.
Methods: To evaluate the extent and duration of selective Aurora A engagement required for tumour shrinkage, a dose fractionation study design was employed. Using a 40 mg/kg total daily dose as a guide, Compound X was administered orally to xenograft tumour-bearing mice at 10 mg/kg QID, 20 mg/kg BID and 40 mg/kg QD for 14 days, with an additional comparison group at 40 mg/kg Q2D, with drug plasma concentration, biomarker (phosphorylated Aurora A; p-AurA) and tumour size data collected throughout the study period. The resulting data were analysed in a sequential manner using empirical PK, PK/p-AurA biomarker and PK/tumour size model structures. Following this tool compound evaluation, the PK and PK/biomarker relationship for LY3295668 was subsequently assessed and, once adjusted for PK and potency, its tumour shrinkage was predicted using the Compound X PK/tumour size model.
Results: For Compound X, a one compartment PK model and simple Emax models successfully described its oral disposition and relationships between PK and p-AurA inhibition, and PK and tumour growth inhibition. The same PK and PK/p-AurA biomarker model structures also sufficiently described the data obtained for LY3295668, with a difference in in vivo potency of approximately 2-fold. Notably, Compound X-mediated tumour shrinkage exhibited a steep PK/PD relationship with an estimated IC50 which was equivalent to the PK/p-AurA IC90. This comparative analysis indicates selective Aurora A inhibition-mediated tumour shrinkage is driven by extended time at or above 90% target inhibition. Using the PK/PD relationships established for Compound X, and adjusting for PK and potency, the tumour shrinkage mediated by LY3295668 was successfully predicted across a range of doses.
Conclusion: The quantitative pharmacology of selective Aurora A inhibition was investigated using a tool compound (Compound X) and successfully predicted for subsequent compounds, of which LY3295668 was advanced to clinical evaluation. This PK/PD evaluation of selective Aurora A inhibitors during a drug discovery programme enabled informed design and selection of compounds with greatest potential for clinical efficacy.
Reference: PAGE 27 (2018) Abstr 8420 [www.page-meeting.org/?abstract=8420]
Poster: Drug/Disease Modelling - Oncology