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

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...

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Published inBasic & clinical pharmacology & toxicology Vol. 122; no. 6; pp. 577 - 587
Main Authors Tohyama, Kimio, Sudo, Miyako, Morohashi, Akio, Kato, Suguru, Takahashi, Junzo, Tagawa, Yoshihiko
Format Journal Article
LanguageEnglish
Published Oxford Wiley Subscription Services, Inc 01.06.2018
Subjects
Absorption
Bioavailability
Blood circulation
Brain
Breast cancer
Central nervous system
Dogs
Excretion
Feasibility studies
Glycoproteins
Hydroxylation
Incubation
Intestine
Liability
Liver
Mental disorders
Metabolism
Metabolites
Microsomes
Oral administration
Pharmacology
Pyrazole
Rats
Rodents
Schizophrenia
Substrates
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Summary: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).
ISSN:1742-7835
1742-7843
DOI:10.1111/bcpt.12964