A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor

Abstract

RationaleSchizophrenia is a complex neuropsychiatric disorder characterized, in part, by impaired dopamine signaling. TAK-063 is a selective inhibitor of phosphodiesterase 10A, a key regulator of intracellular signaling pathways that is highly expressed in the striatum.ObjectiveSafety, tolerability, and pharmacokinetics of TAK-063 were evaluated in a phase 1 study.MethodsHealthy Japanese and non-Japanese volunteers were randomized into dose cohorts of 3, 10, 30, 100, 300, and 1000 mg. Each fasting volunteer randomly received a single dose of TAK-063 or placebo. Individuals from the 100-mg cohort also received a post-washout, 100-mg dose under fed conditions. A total of 84 volunteers enrolled (14 per cohort).ResultsThe most common drug-related adverse events (AEs) were somnolence (33.3 %), orthostatic tachycardia (19.7 %), and orthostatic hypotension (9.1 %). The three severe AEs recorded occurred at the highest doses: orthostatic hypotension (n = 1; 300 mg) and somnolence (n = 2; 1000 mg). There were no deaths, serious AEs, or discontinuations due to AEs. TAK-063 exposure increased in a dose-dependent manner. Median T max was reached 3 to 4 h postdose. Fed conditions slowed absorption (T max = 6 h) and increased oral bioavailability. Renal elimination was negligible. Safety and pharmacokinetic parameters were similar between Japanese and non-Japanese subjects. Impairments in cognitive function consistent with the effects of other sedative or hypnotic agents were detected using a validated, computerized cognition battery, CNS Vital Signs.ConclusionsTAK-063 was safe and well tolerated at doses up to 1000 mg and demonstrated a pharmacokinetic profile supporting once-daily dosing. Further evaluation of the clinical safety and efficacy of TAK-063 is warranted.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-016-4412-9) contains supplementary material, which is available to authorized users.

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

“…The concentrations of unchanged parent drug were below the lower limit of quantification in rat and dog urine, and <1% of the dose in rat bile, suggesting negligible importance of urinary and biliary excretion of TAK-063 in both species. This was in agreement with the low renal clearance of TAK-063 (CL r <7 mL/h) observed in a phase 1 study of TAK-063 at a dose range of 3 to 1000 mg (Tsai et al 2016). Unchanged TAK-063 accounted for 41.5 and 60.8% of the dose in faeces of fed rats and dogs, respectively, after oral administration, indicating that TAK-063 may have poor solubility.…”

“…However, exposure levels of M-I were much lower than those of parent drug TAK-063 in dogs and rats. In contrast, M-I in human beings showed similar PK properties to TAK-063, with M-I-to-parent ratios of approximately 1 for C max , AUC (0-tlqc) and AUC (0-inf) (Tsai et al 2016). Interestingly, plasma protein binding of M-I is higher than TAK-063 (≥99% versus 96%, table 5), suggesting that the free fraction of TAK-063 is significantly higher IC 50 , half-maximal inhibitory concentration; M-I, TAK-063 metabolite.…”

“…These differences could be explained by higher plasma protein binding of TAK-063 in rats (>99%) than in dogs and human beings (95-96%). In a phase 1 clinical study of safety, tolerability and PK, TAK-063 exposure increased with dose within the 3 mg to 1000 mg dose range [14]. Clearance (CL/F) and volume of distribution (Vz/F) of TAK-063 also increased with dose, ranging from 14.0 to 232.0 L/h and from 407 to 5570.7 L, respectively [14].…”

“…In a phase 1 clinical study of safety, tolerability and PK, TAK-063 exposure increased with dose within the 3 mg to 1000 mg dose range [14]. Clearance (CL/F) and volume of distribution (Vz/F) of TAK-063 also increased with dose, ranging from 14.0 to 232.0 L/h and from 407 to 5570.7 L, respectively [14]. The rat tissue distribution study indicated that radioactivity was distributed rapidly into tissues including the brain after oral administration of [ 14 C]TAK-063.…”

“…After IV infusion of M-I for 4 hr at a dose of 0.1 mg/ kg/h, the M-I brain-to-plasma ratio ranged from 0.04 to 0.07, suggesting minimal brain penetration for M-I in rats. In comparison, the ratio for TAK-063 at 3 hr after oral administration of 14 [C]TAK-063 was approximately 1.…”