SP428A RANDOMIZED, SINGLE-CENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTIPLE-DOSE, PHASE 1 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS (PK), AND PHARMACODYNAMICS (PD) OF TAK-272 IN HEALTHY ADULT NON-ELDERLY AND ELDERLY MALE SUBJECTS

Abstract

INTRODUCTION AND AIMS: TAK‐272 is a direct renin inhibitor with potential target indications for cardiovascular/renal disease. This study evaluated the safety and PK/PD of multiple oral administrations of TAK‐272 in healthy adult non‐elderly and elderly male subjects. METHODS: This was a randomized, double‐blind, phase 1 study. Elderly (age, 65‐85 yrs) or non‐elderly (age, 20‐45 yrs) healthy Japanese male subjects with body mass index of 18.5‐25.0 kg/m2 were eligible. Subjects were randomized within 1 of 3 cohorts to receive TAK‐272 (n=9) or placebo (n=3): cohort 1 (TAK‐272 80 mg; non‐elderly), cohort 2 (TAK‐272 160 mg; non‐elderly), or cohort 3 (TAK‐272 80 mg; elderly). TAK‐ 272 or placebo tablets were administered orally, once‐daily for 7 days. Dietary salt intake was not restricted. Safety was assessed throughout the study. Plasma renin activity (PRA) and plasma active renin concentration (PRC) were measured as PD evaluation. RESULTS: 36 subjects were randomized and received study drug. Plasma concentration of unchanged TAK‐272 (TAK‐272F) reached steady state by Day 7. Mean half‐life (T1/2) of TAK‐272F was longer in elderly subjects than in non‐elderly subjects on Day 7 (Table). The area under the plasma‐concentration time curve (AUC0‐τ) and maximum plasma concentration (Cmax) of TAK‐272F were higher in elderly than in non‐elderly subjects (52% and 39% higher, respectively). PRA was rapidly inhibited at the 80‐mg and 160‐mg doses in non‐elderly subjects and also at the 80‐mg dose in elderly subjects. Strong inhibition of PRA was observed for 7 days and was maintained until 71 hrs after the last administration of TAK‐272. PRC increased in non‐elderly and elderly subjects (Table). Increase from baseline in PRC was smaller in elderly than in non‐elderly subjects during the 7‐day treatment period and until 71 hrs after last study drug administration. In non‐elderly subjects, rates of treatmentemergent adverse events (TEAEs) were 16.7% (1/6 subjects) in the placebo group, 22.2% (2/9) in the TAK‐272 80‐mg group, and 22.2% (2/9) in the TAK‐272 160‐mg group. In elderly subjects, rates of TEAEs were 33.3% (1/3) in the placebo group and 33.3% (3/9) in the TAK‐272 80‐mg group. Alanine aminotransferase increased was the most common AE among non‐elderly subjects (n=3); headache and diarrhea were the most common AEs among elderly subjects (n=2 each). All TEAEs were mild in intensity, except for 1 (moderate urticaria) in the non‐elderly, TAK‐272 80‐mg group. There were no deaths or serious AEs. CONCLUSIONS: Multiple oral administrations of TAK‐272 (80 or 160 mg) for 7 days were safe and well tolerated in non‐elderly subjects; the 80‐mg dose was also safe and well tolerated in elderly subjects. The plasma concentration of TAK‐272F reached steady state by Day 7. The AUC and Cmax of TAK‐272F were greater in elderly than in non‐elderly subjects. PRA was rapidly inhibited at either dose; strong inhibition of PRA was observed for 7 days, and maintained until 71 hrs after the last administration of TAK‐272.