Pre-clinical Characterization of Absorption, Distribution, Metabolism and Excretion Properties of TAK-063.

Abstract

TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine. TAK-063 can also cross the blood-brain barrier. TAK-063 was metabolized mainly by CYP2C8 and CYP3A4/5, while incubation with human liver microsomes produced the major human metabolite, M-I as well as several unknown minor metabolites. Metabolism of TAK-063 to M-I occurs through hydroxylation of the mono-substituted pyrazole moiety. In vitro, TAK-063 was observed to inhibit CYP2C8, CYP2C19 and P-gp with IC50 values of 8.4, 12 and 7.13 μM, respectively. TAK-063 was primarily excreted in the faeces in rats and dogs with M-I as a predominant component. The pre-clinical data from these ADME studies demonstrate a favourable pharmacokinetic profile for TAK-063 with good brain distribution supporting the feasibility of targeting central nervous system regions involved in schizophrenia pathophysiology. TAK-063 has recently been investigated in a phase 2 clinical trial (NCT02477020).

• Authors: Kimio Tohyama, Miyako Sudo, Akio Morohashi, Suguru Kato, Junzo Takahashi, Yoshihiko Tagawa
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 122 Issue 6 Pg. 577-587 (Jun 2018) ISSN: 1742-7843 [Electronic] England
• PMID: 29345044 (Publication Type: Journal Article)
• Copyright: © 2018 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Chemical References

• 1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
• Antipsychotic Agents
• Cytochrome P-450 Enzyme Inhibitors
• Phosphodiesterase Inhibitors
• Pyrazoles
• Pyridazines
• PDE10A protein, human
• Phosphoric Diester Hydrolases

Topics

• Animals
• Antipsychotic Agents (metabolism, pharmacokinetics)
• Biotransformation
• Caco-2 Cells
• Cytochrome P-450 Enzyme Inhibitors (pharmacology)
• Dogs
• Half-Life
• Humans
• Intestinal Absorption
• Male
• Phosphodiesterase Inhibitors (metabolism, pharmacokinetics)
• Phosphoric Diester Hydrolases (drug effects)
• Protein Binding
• Pyrazoles (metabolism, pharmacokinetics)
• Pyridazines (metabolism, pharmacokinetics)
• Rats
• Rats, Long-Evans
• Rats, Sprague-Dawley
• Tissue Distribution