Safety and Pharmacokinetics of High-Dose TAS-303 in Healthy Japanese Volunteers

A Single-Center, Single-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multiple-Ascending-Dose Study

Significance 

Stress urinary incontinence is the most common type of urinary incontinence in women. It occurs when there is an involuntary leakage from the urethral orifice associated with effort or physical exertion or on sneezing or coughing. Globally, this condition has been found to severely compromise the quality of life of women. It is therefore expected that the treatment of stress urinary incontinence will have a remarkable social impact on women. Currently, the development of safe and effective drugs for stress urinary incontinence is being awaited. TAS-303 (4-piperidinyl 2,2-diphenyl-2-[propoxy1,1,2,2,3,3,3-d7] acetate hydrochloride) is a noradrenaline reuptake inhibitor developed by Taiho Pharmaceutical Co., Ltd in Japan. A previous ex vivo study showed that TAS303 caused a concentration dependent increase in urethral contraction in rats. Another study, showed that in vivo, TAS-303 resulted in a dose dependent increase in urethral pressure as well as leak point pressure in rats. Based on these results, it is expected that TAS-303 will likely contribute to the remission of incontinence and improve the quality of life of patients with stress urinary incontinence.

Doctor Ryuzo Hanada from SOUSEIKAI Sumida Hospital in Japan led a clinical study he explored the safety and tolerability of TAS-303 when administered as multiple oral doses of 8 to 18mg once daily for 16 days, in healthy subjects. In addition, the pharmacokinetics and inhibitory effect of TAS-303 on hepatic cytochrome P450 (CYP) 3A activity was also investigated. The results showed that TAS-303 had a good pharmacokinetic profile that was dose-proportional across the doses used over the 16-day multiple administration period, and within this dose range, TAS-303 might inhibit hepatic CYP3A activity. The original research article is now published in the Journal of Clinical Pharmacology in Drug Development.

The clinical team found the incidence of adverse events in the placebo and TAS-303 (8,10,12,15,and 18mg) groups were similar and increasing doses of TAS-303 did not result in any increase in the incidence of adverse events. The overall incidence of adverse events was higher in the placebo group compared to the TAS-303 group. None of the subjects discontinued the study on account of an adverse event. In all the subjects treated with placebo or TAS-303, the most common adverse event reported was observed to be diarrhea. Diarrhea was also the only reported treatment-related adverse event that was observed in 1 subject in the TAS-303 18 mg group and it was mild and resolved without treatment.

TAS-303 was found to have an increase in its mean plasma concentration that was dose dependent and reached a steady state between day 11 and day 13. The urinary hydroxycortisol /cortisol ratio and formation clearance of hydroxycortisol, used as endogenous hepatic CYP3A activity markers were found to be significantly decreased at TAS-303 doses ranging from 10 to 18 mg and 8 to 18 mg respectively.

One limitation of the study is that it was conducted only in healthy men although stress urinary incontinence also affects women. Moreover, it only recruited Japanese men, which would make it difficult to generalize the findings to other ethnic populations.

In a nutshell, the clinical study has demonstrated that TAS-303 is safe and well tolerated at a dose of 8 to 18 mg. The findings also suggest that hepatic CYP3A activity might be inhibited by multiple doses of TAS-303 at doses ranging from 8 to 18 mg. Future clinical studies will focus on demonstrating whether TAS-303 at optimal doses can have the therapeutic efficacy for treatment of stress urinary incontinence.

About the author

Ryuzo Hanada, MD graduated from National Defense Medical College. He is a board-certified supervisor clinical pharmacologist, acute care physician and registered anesthesiologist. He joined SOUSEIKA Sumida Hospital in 2008 and is currently working as an investigator, mainly on Phase 1 trials.

Reference

Hanada R. Safety and Pharmacokinetics of High-Dose TAS-303 in Healthy Japanese Volunteers: A Single-Center, Single-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multiple-Ascending-Dose Study. Clin Pharmacol Drug Dev. 2020;9(8):961-971.

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