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 Pgp with IC 50 values of 8.4, 12 and 7.13 lM, 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).Phosphodiesterase 10A (PDE10A) acts as an important regulator of signal transduction by degrading the second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate [1,2]. PDE10A is preferentially expressed in the medium spiny neurons of the striatum, a region of critical importance for domains that are disrupted in patients with schizophrenia [3][4][5].Current treatments often do not adequately address the multifaceted clinical symptomatology of schizophrenia [6]. In addition, antipsychotics are associated with cardiometabolic disturbances and cardiovascular morbidity that worsen longterm outcomes [7]. Because of the shortcomings in current treatment options for schizophrenia, PDE10A inhibition by TAK-063 is being evaluated as a new therapeutic strategy.TAK-063 is a potent and highly selective PDE10A inhibitor [8,9]. Furthermore, TAK-063 has demonstrated pre-clinical efficacy in animal models of schizophrenia. TAK-063 produced dose-dependent antipsychotic-like effects in rodent models of induced psychosis [10]. In rodents, PDE10A inhibition by TAK-063 also improved cognitive functions impaired in schizophrenia [11]. TAK-063 exhibits a favourable safety profile in a rodent study [12]. To understand the mechanism of these efficacy and safety profiles of TAK-063, the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 were investigated.In general, ADME properties using radiolabelled materials in animals and human beings are required for inclusion in the New Drug Application for new molecular entities. This report he...