LB-021 - TRANSLATION OF RAT TO HUMAN BRAIN CONCENTRATIONS USING PBPK MODELING CONFIRMS HIGH BRAIN PENETRATION OF THE TYK2/JAK1 INHIBITOR BHV-8000.

R. Bertz¹, L. Shireman², H. Jones², D. Heller³, R. Bhardwaj³, E. Thompson¹, E. Dierks¹, P. Ackerman¹, N. Kozauer¹, I. Qureshi¹, V. Coric¹; ¹Biohaven, New Haven, CT, United States, ²Certara UK, Sheffield, United Kingdom, ³Certara USA, Radnor, PA, United States.

Background: TYK2 and JAK1 signaling play key roles in the mechanisms underlying the onset and progression of neuroinflammatory and neurodegenerative diseases including Multiple Sclerosis (MS), Parkinson’s Disease (PD), Alzheimer’s Disease (AD) and amyloid-related imaging abnormalities (ARIA) associated with anti-amyloid therapies. BHV-8000 is a novel, oral, highly selective dual TYK2/JAK1 inhibitor that is being developed as a novel treatment strategy against these conditions.

Methods: A physiologically based pharmacokinetic (PBPK) model was developed using the Simcyp Simulator V23. Physicochemical and in vitro data for BHV-8000, including the fraction unbound in plasma as well as in rat brain, permeability in cell lines, and solubility, were used as input. Clinical concentration-time profiles were used to refine the volume of distribution concordant with that observed in preclinical species; observed oral clearance was used to back-calculate hepatic intrinsic clearance. Measurements of efflux transporter kinetics in transfected MDCK cell lines were optimized to capture observed brain concentrations of BHV-8000 in rat then adjusted with a relative-activity factor for use in the human model. The PBPK model in human was developed using a subset of available clinical data, and validated with remaining clinical data, including a cohort with cerebrospinal fluid (CSF) concentrations available, then used to predict human systemic and brain exposures of BHV-8000.

Results: The predicted mean Kp,uu,brain was 0.539, and measurements of CSF were predicted to be similar to unbound brain concentrations. Simulated geometric mean (90% CI) unbound brain Cmax and AUCtau for 20mg ER QDay are 71.3 (65, 78) ng/mL and 1221 (1105, 1350) ngxhr/mL, respectively. Mean steady-state unbound human brain concentrations were predicted to exceed the TYK2 EC50 at doses of 10 and 20 mg ER QDay.

Conclusion: A human PBPK model for the TYK2/JAK1 inhibitor BHV-8000 was developed and used to simulate unbound human brain concentrations. Doses of 10 and 20mg ER QDay are expected to produce adequate free brain concentrations for target engagement of BHV-8000 for the management of CNS neuroinflammatory conditions including MS, PD and AD.