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GSK2330672 is an inhibitor of the ileal bile acid transporter, designed to have minimal systemic exposure, and is under development as a potential therapeutic for pruritus associated with primary biliary cholangitis and other cholestatic liver diseases. A phase 1, double‐blind, placebo‐controlled, 4‐period crossover study was conducted to evaluate the safety, tolerability, and pharmacokinetic/pharmacodynamic characteristics of GSK2330672 in healthy Japanese participants. Sixteen healthy male participants received single oral doses of GSK2330672 (10‐180 mg) or placebo in each period. No serious adverse events and no adverse events leading to study discontinuation or withdrawal were reported. Drug‐related adverse events reported included gastrointestinal symptoms (mostly diarrhea) and positive fecal occult blood tests, and were all mild and resolved without any interventions. GSK2330672 was undetectable in the majority of participants' plasma. Pharmacodynamic observations included a tendency for total serum bile acids to reduce and for serum 7α‐hydroxy‐4‐cholesten‐3‐one, a key intermediate of bile acid synthesis, to increase with increasing doses of GSK2330672. In the context of recently published indications of potential efficacy for cholestatic pruritus in non‐Japanese populations, these data support further evaluations of GSK2330672 in Japanese patients. [ABSTRACT FROM AUTHOR]

The aim of the study was to assess the safety, tolerability, and pharmacokinetics of single and repeat doses of nemiralisib administered via a dry powder inhaler to healthy Japanese subjects. This was a single‐center, double‐blind, randomized, placebo‐controlled, parallel, single‐ and repeat‐ascending‐dose study. Thirty‐six healthy Japanese male subjects were randomized to receive either 1 dose strength of nemiralisib or placebo. The study consisted of a screening period, a single‐dose session (session 1), a repeat‐dose session (session 2), a 10‐day washout period between the sessions, and then a follow‐up visit 10 ± 1 days after the last dose of session 2. No serious adverse events were reported. No clinically significant abnormalities were found in clinical laboratory results, vital signs, or spirometry results. Generally, exposure (maximum observed plasma concentration [Cmax] and area under the concentration‐time curve [AUC]) increased with dose in an approximately proportional manner. Plasma Tmax was achieved rapidly at approximately 0.08 hours, and the terminal elimination half‐life (T1/2) was approximately 40 hours. Tmax and T1/2 did not change between days or doses in the single‐ and repeat‐dose sessions. Following 10 daily doses of 200, 500, and 700 μg nemiralisib, accumulation was observed, and the ratios (session 2, day 10:session 1) for Ro(AUC0‐24) and R(Cmax) were 2.4‐3.0 and 1.5‐1.7, respectively. Steady state was achieved by 6‐7 days, based on trough observed plasma drug concentration (Ctrough) values. [ABSTRACT FROM AUTHOR]

Animal models of mental disorders as well as physical disorders have been useful tools to elucidate pathophysiology of the complex disorders and develop new therapeutics. Transgenic mice including gene knockout animals have been produced by gene targeting technology. Monoamine system which is target of antipsychotics and antidepressants has very important roles in pathology of functional psychosis. In this review, we would like to introduce monoamine transporter knockout mice that we had generated as animal models of mental disorders including schizophrenia and drug abuse.