Abstract
PurposeTAK-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.MethodsPK, 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.ResultsThe 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.ConclusionA 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.
Highlights
TAK-831 (4-hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one) is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO)
A quantitative mechanistic model for concentration- and time-dependent nonlinear PK/target occupancy (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
Summary
TAK-831 (4-hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one) is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO). DAAO is a peroxisomal enzyme active towards neutral D-amino acids, and has been linked to the metabolism of D-serine. D-serine has been demonstrated to be a co-agonist of N-methyl-D-aspartate (NMDA) glutamate receptors that, along with glutamate, mediates NMDA receptor transmission, synaptic plasticity and other physiological functions. TAK-831 has shown to increase D-serine levels in the cerebellum of normal mice and demonstrated a positive effect in mouse models associated with negative symptoms and cognitive impairment in schizophrenia [7]. In the delayed paradigm of conditioned eyeblink behavior in mice, a model of cerebellar-based associative learning, TAK-831 showed improvement in the acquisition of the conditioned response and in reversing the scopolamine induced deficit. Based on the evidence above, TAK-831 is currently under development for the treatment of cognitive impairment associated with schizophrenia (CIAS), and negative symptoms of schizophrenia [8]
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