Mechanistic Multilayer Quantitative Model for Nonlinear Pharmacokinetics, Target Occupancy and Pharmacodynamics (PK/TO/PD) Relationship of D-Amino Acid Oxidase Inhibitor, TAK-831 in Mice.

TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO) currently under clinical development for schizophrenia. In this study, a mechanistic multilayer quantitative model that parsimoniously connects pharmacokinetics (PK), target occupancy (TO) and D-serine concentrations as a pharmacodynamic (PD) readout was established in mice. PK, TO and PD time-profiles were obtained in mice and analyzed by mechanistic binding kinetics model connected with an indirect response model in a step wise fashion. Brain distribution was investigated to elucidate a possible mechanism driving the hysteresis between PK and TO. The observed nonlinear PK/TO/PD relationship was well captured by mechanistic modeling framework within a wide dose range of TAK-831 in mice. Remarkably different brain distribution was observed between target and reference regions, suggesting that the target-mediated slow binding kinetics rather than slow penetration through the blood brain barrier caused the observed distinct kinetics between PK and TO. A quantitative mechanistic model for concentration- and time-dependent nonlinear PK/TO/PD relationship was established for TAK-831 in mice with accounting for possible rate-determining process. The established mechanistic modeling framework will provide a quantitative means for multilayer biomarker-assisted clinical development in multiple central nervous system indications.