(M1230-10-65) Pharmacokinetic Characterization of a Novel COVID-19 Inhibitor OJT010 in a Rat Model

Purpose: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the etiological agent responsible for the COVID-19 global pandemic. We identified a novel compound, OJT010, as an inhibitor of the host receptor ACE2 that is required for SARS-CoV-2 viral entry into the host cell.

Methods: Single dose crossover pharmacokinetic studies were conducted in jugular vein cannulated adult male Sprague Dawley rats to evaluate oral bioavailability of OJT010. Multiple dose steady-state pharmacokinetic studies were further conducted in the rats to evaluate the drug accumulations in the lungs. Serial timed blood samples were collected before and after dose administration. Plasma concentrations of OJT010 were measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were obtained using WinNonlin program.

Results: Following a 50 mg/kg IV administration (n=3), OJT010 showed a bi-exponential disposition with a mean terminal half-life of 7.3 hours. Mean maximum plasma concentration (C_max) was 2560 ng/mL at 25 min after a single 250 mg/kg oral dosing (n=3). Absolute oral bioavailability of OJT010 was 15.5% in the crossover study. In another set of study, C_max was 2176, 827 and 1118 ng/mL following a single oral 250 mg/kg (n=3), a daily oral 250 mg/kg for 5 days (n=3), and a daily oral 400 mg/kg for 5 days administration (n=3), respectively. A dose-normalized Turkey post hoc analysis showed significant decrease in C_max between the single versus multiple 250 mg/kg oral dosing (P=0.05). The observed decrease of drug exposure following multiple administration was probably due to self-induced hepatic drug metabolism. Interestingly, we observed significant accumulation of the drug in the lungs with an average ratio of C_lung/C_plasma at 17.7. Further studies are ongoing to explore mechanisms of the unique tissue drug disposition and metabolism using in vitro cell culture and PBPK modeling.

Conclusion: Pharmacokinetics of OJT010 were characterized using rat as an animal model. The drug appears to accumulate in the lungs.

Acknowledgements: This work is supported in part by a NIMHD U54MD007605 grant at Texas Southern University