Mechanistic Multilayer Quantitative Model for Nonlinear Pharmacokinetics, Target Occupancy and Pharmacodynamics (PK/TO/P
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RESEARCH PAPER
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 Tomoki Yoneyama 1 & Sho Sato 1 & Andy Sykes 2 & Rosa Fradley 3 & Stuart Stafford 3 & Shyam Bechar 3 & Eimear Howley 3 & Toshal Patel 3 & Yoshihiko Tagawa 1 & Toshiya Moriwaki 1 & Satoru Asahi 1 Received: 8 May 2020 / Accepted: 24 July 2020 # The Author(s) 2020
ABSTRACT Purpose 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. Methods 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. Results 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. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11095-020-02893-x) contains supplementary material, which is available to authorized users. * Tomoki Yoneyama [email protected]
1
Present address: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
2
Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Cambridge Ltd, Cambridge, UK
3
Pharmacology, Takeda Cambridge Ltd, Cambridge, UK
Conclusion 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.
KEYWORDS D-amino acid oxidase inhibitor . PK/PD, multilayer quantitative model . TAK-831 . target occupancy
ABBREVIATIONS BBB BCRP Boc-L-Cys CIAS CNS CSF DAAO FOCE GluRĪ“2 HPLC IC50 i.v. LC/MS/ MS NMDA OPA PET P-gp p.o.
Blood brain barrier Breast cancer resistance protein N-tert-butyloxycarbonyl-L-cysteine Cognitive impairment associated with schizophrenia Central nervous system Cerebrospinal fluid D-amino acid oxidase First-order conditional estimation Delta 2 glutamate receptor High performance liquid chromatography 50% inhibitory concentration Intravenously Liquid chromatography-tandem mass s
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