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A Mass Balance Study of [14C] TAS5315 in Healthy Adult Subjects

A Mass Balance Study of [14C] TAS5315 in Healthy Adult Subjects

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The subjects in the PK Evaluable Population were all male, with a median age of 22.0 years (range: 18-33 years). Median BMI was 20.80 kg/m2 (range: 18.6-23.6 kg/m2). There were no subjects with a past medical history or complications.

Six eligible subjects were enrolled, all of whom received the investigational product. All of the 6 subjects who received the investigational product were evaluable for PK.

-The safety analysis population consisted of 6 subjects in the Treated Population. An AE was noted in 1 subject. This AE was diarrhoea, and the severity classification was mild. The event was considered not related to the investigational product and resolved in 2 days after the onset without treatment. -No serious AEs or adverse reactions, AEs or adverse reactions leading to treatment discontinuation, AEs of special interest (AESIs), or AEs or adverse reactions leading to death were observed.

-When 6 healthy adult male subjects were administered a single oral dose of 4 mg of TAS5315-containing [14C]TAS5315 (about 1 MBq), 90.25% (mean) of the administered radioactivity was cumulatively excreted in urine and feces by 168 hours after administration. 20.08% (mean) and 70.18% (mean) of the administered radioactivity were excreted in urine and feces, respectively, indicating that the major route of excretion of radioactivity after administration of [14C]TAS5315 is fecal excretion, followed by urinary excretion. -Tmax of plasma and blood radioactivity and plasma TAS5315 after [14C]TAS5315 administration were all 1 hour (median). TAS5315 in plasma was rapidly eliminated, with a T1/2 of 1.157 hours (geometric mean). On the other hand, the elimination of radioactivity in plasma and blood was slow; T1/2 values of plasma and blood radioactivity in each subject were 202-302 hours and 231-424 hours, respectively. The slow elimination of radioactivity in plasma and blood was considered to be due to unextractable radioactivity. -The mean blood/plasma radioactivity concentration ratio was 0.6797-0.9434 up to 168 hours after administration, suggesting that radioactivity after administration is distributed to plasma and blood cell components. -TAS5315 was the major component in the pooled plasma sample, accounting for 62.1% of the recoverable radioactivity. No metabolites accounted for > 10% of the total plasma exposure. After oral administration, TAS5315 orally administered was presumed to be metabolized by multiple metabolic pathways including oxidation, dihydrodiolation or reduction of acryl amide moiety, glucuronidation, hydrolysis, and cysteine conjugation. Almost no unchanged TAS5315 was detected in urine or feces samples, indicating that renal excretion is not the major elimination pathway of TAS5315.

-Metabolite profile and routes of excretion after a single oral dose of TAS5315 were identified. The major route of excretion was fecal excretion, followed by urinary excretion. Almost no unchanged TAS5315 was detected in urine or feces, indicating that renal excretion is not the major elimination pathway. No metabolites accounted for > 10% of the total plasma exposure. -The only AE observed was mild diarrhoea. These results confirmed that TAS5315 has no safety problems, and its tolerability is good.

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IPD data will not be shared according to the Sponsor policy on data sharing. Taiho clinical trial information disclosure policy may be found at https://www.taiho.co.jp/en/science/policy/clinical_trial_information_disclosure_policy/index.html

https://jrct.mhlw.go.jp/latest-detail/jRCT2071230061

Ali Nasermoaddeli

Taiho Pharmaceutical Co., Ltd.

1-27 Kandanishiki-cho, Chiyoda-ku, Tokyo

th-tas5315_clinical@taiho.co.jp

Suto Kotaro

Taiho Pharmaceutical Co., Ltd.

1-27 Kandanishiki-cho, Chiyoda-ku, Tokyo

+81-3-3293-2455

th-tas5315_clinical@taiho.co.jp

Complete

Oct. 30, 2023

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1) Aged 18 or older and younger than 40 years at the time of consent
2) Weigh at least 45.0 kg at the time of screening tests with a body mass index (BMI, weight [kg]/[height {m}]2) ranging from 18.0 to < 25.0 kg/m2
3) Blood pressure and body temperature obtained in screening tests within the following ranges
a Systolic blood pressure (in supine position), 90 to 139 mmHg
b Diastolic blood pressure (in supine position), 40 to 89 mmHg
c Body temperature ranging from 35.0 to 37.4
4) Judged to be healthy by the investigator based on the examination findings (subjective symptoms and objective findings), blood pressure, pulse rate, body temperature, 12-lead ECG, and laboratory tests (hematology test, biochemistry test, and urinalysis) at the time of screening tests

1) Had any concurrent disease (including symptoms and signs; however, diseases that do not affect evaluations in the study such as asymptomatic pollinosis and wart are excluded)
2) Had any severe disease history that may recur during the study period.

Male

healthy adult males

Orally administration of 8 mL (containing 4 mg of TAS5315 and about 1 MBq of administered radioactivity) of the prepared solution

-Plasma and blood radioactivity concentrations, plasma TAS5315 concentrations and their pharmacokinetic parameters, and blood/plasma radioactivity concentration ratio
-Excretion and rate of radioactivity in urine and feces, cumulative excretion and cumulative excretion rate
-Total amount and rate of excretion of radioactivity in urine and feces, total amount and rate of cumulative excretion
-Metabolite profile and structural estimation of TAS5315 in plasma, urine and feces

+81-92-283-7701

Oct. 13, 2023

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