Drug-drug interaction between TAS-303 and simvastatin/midazolam in healthy subjects

• Published in: Proceedings for Annual Meeting of The Japanese Pharmacological Society Vol. WCP2018; p. PO2-14-20
• Main Authors: Kumagai, Yuji, Fujita, Tomoe, Aso, Masako, Amano, Hideki, Sasaki, Yoshinobu, Kawai, Masaki, Takenaka, Toru, Nagaoka, Makoto, Hoashi, Koichiro
• Format: Journal Article
• Language: English
• Published: Japanese Pharmacological Society 2018
• Subjects: Clinical trial; Drug-drug interaction; TAS-303
• ISSN: 2435-4953; 2435-4953
• DOI: 10.1254/jpssuppl.WCP2018.0_PO2-14-20

Background: TAS-303, a selective noradrenaline reuptake inhibitor, is currently at the stage of Phase II development for stress urinary incontinence in Japan. In nonclinical study, TAS-303 has a time-dependent inhibitory potential toward Cytochrome P450 (CYP) 3A. In order to evaluate the effect of TAS-303 on CYP3A activity and the safety of TAS-303 administered in combination with simvastatin/midazolam, we conducted a clinical trial in healthy adult subjects (n=12).Methods: The major objective is to investigate the effect of TAS-303 3 mg on activity of CYP3A by evaluating the pharmacokinetics (PK) of simvastatin at an oral dose of 5 mg and midazolam at an intravenous dose of 1 mg. Simvastatin and midazolam are sensitive substrates susceptible to PK drug interactions with CYP3A. This study was a single-centre, open-label, single-group study. Procedures of this study are shown in Figure 1. The point estimates for the geometric mean ratio for the PK parameters of simvastatin/midazolam and their 90% CIs in the presence and absence of TAS-303 were calculated. Results: The point estimates (90% CIs) for the geometric mean ratio for the Cmax and AUC0-t of simvastatin were 1.326 (1.089 to 1.615) and 1.420 (1.041 to 1.938) respectively. The point estimates (90% CIs) for the geometric mean ratio for the C0 and AUC0-t of midazolam were 1.088 (0.935 to 1.265) and 1.090 (1.030 to 1.154) respectively.Adverse events were headache (1 subject) and diarrhoea (1 subject) in the simvastatin monotherapy period; and paraesthesia (1 subject) and diarrhoea (1 subject) in the TAS-303 plus simvastatin combination period; and somnolence (8 subjects), vertigo (1subject), and monoparesis (1 subject) in the midazolam monotherapy period; and insomnia (1 subject) and somnolence (12 subjects) in the TAS-303 plus midazolam combination period. Conclusions: These study results indicated that TAS-303 3 mg was a weak inhibitor of CYP3A in the small intestine, but was no effect on CYP3A in the liver. In addition, no safety-significant interaction in combination with simvastatin/midazolam was observed. These results showed that there were no tolerability concerns on TAS-303 in combination with simvastatin/midazolam.