EP-014 - ESTIMATION OF NOVEL BISPECIFIC T-CELL ENGAGER (BiTE®) MOLECULE PHARMACOKINETICS IN CYNOMOLGUS MONKEY FROM STRUCTURALLY-SIMILAR BiTE MOLECULE DATA.

I. Vuu¹, M. Lutteropp², B. Rock³, B. Houk¹; ¹Amgen Inc., Thousand Oaks, CA, USA, ²Amgen Inc., Munich, Germany, ³Amgen Inc., South San Francisco, CA, USA.

Background: Large molecule therapeutics are often cross-reactive with a cynomolgus monkey (cyno) target. Cyno pharmacokinetic (PK) data is often used for human PK predictions, where cross-reactivity with cyno target may be informative for target-mediated drug disposition. In the case where there is no orthologous cyno target, cyno PK may be estimated if there is an existing cyno PK database from structurally-similar molecules. In this study, we used a database of cyno and BiTE® (human bispecific T-cell engager) molecule PK data to estimate cyno PK of a novel BiTE molecule which targets a complex not present in cyno.

Methods: Cyno concentration-time data were collected from 12 BiTE molecules. A population PK (popPK) model was used to describe the PK of all BiTE molecules. Target was tested as a covariate on clearance (CL) and volume (V). The analysis was repeated for BiTE molecules that targeted epitopes with low/no orthologous cyno expression and again with human BiTE PK data.

Results: A two-compartment model described cyno BiTE PK. Individual BiTE molecules had CLs and Vs that varied from -67% to +189% and -49% to +109% of the reference, respectively. Of the BiTE molecules that targeted epitopes with low cyno expression, CLs and Vs varied -43% to +25% and +7% to 17% of the reference, respectively. In humans, CLs and Vs varied -51% to +488% and -49% to +524% of the reference, respectively. PK differences ranked similarly with respect to the same reference BiTE molecule in cyno and humans.

Conclusion: For BiTE molecules with low/no orthologous cyno expression, individual cyno and human BiTE CLs only varied up to 70% while V was similar. These results suggest that using a popPK approach from a subset of BiTE molecules may be useful in predicting cyno and human PK for a novel structurally-similar BiTE molecule which targets a complex not present in cyno.