PII-076 - POPULATION PHARMACOKINETIC (PK)-PHARMACODYNAMIC (PD) MODELING OF VESATOLIMOD, A TLR7 AGONIST IN DEVELOPMENT FOR HIV CURE.

S. Kathman¹, R. Deng², B. Chen², M. Wire², J. Cai², R. Palaparthy², Y. Zheng²; ¹Gilead Sciences, Clemmons, NC, USA, ²Gilead Sciences, Foster City, CA, USA.

Background: Vesatolimod (VES) is an orally administered potent and selective Toll-Like Receptor 7 agonist in development for HIV cure in combination with other therapeutic agents. In clinical studies, VES increased the levels of cytokines/chemokines and IFN-stimulated genes (ISG).

Methods: Population PK-PD modeling was performed using data from 10 completed clinical trials in healthy volunteers (HV), and people living with HIV, HBV, or HCV, to understand the dose-response of VES. A two-compartment model was used to characterize the PK of VES. PD biomarkers (CXCL10, CXCL11, and ISG15) were modeled utilizing indirect response models with zero order synthesis and first order elimination rates, where an Emax function describes the relationship between VES concentration and the fold change in synthesis rates.

Results: The population PK model included a term for food effect on relative bioavailability, dose on relative bioavailability, and population effect (HV, HIV, HBV, or HCV) on clearance. The model showed that increased VES concentrations led to increased responses in CXCL10, CXCL11, and ISG15 with EC50s of 1224-3361, 1436-2253, and 446-750 pg/mL of VES respectively, depending on the assay that was used. The maximum fold increases were 19, 9, and 41, respectively. Based on simulation results, increased VES doses up to 12 mg leads to increased/prolonged PD responses of the biomarkers. The dose response of ISG15, but not CXCL10 and CXCL11, was close to saturation above 8 mg.

Conclusion: The population PK-PD models of VES provided quantitative insight into the dose-response relationship of the immune modulatory effects of VES across different populations on CXCL10, CXCL11 and ISG15. Further characterization of exposure-response for biomarkers and safety endpoints will allow us to establish a benefit-risk ratio to optimize VES dose.