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
Kumi Matsuno, Shingo Tanaka, Takeshi Hashimoto, Hiroyuki Nakamichi, Emiko Komura · Nephrology Dialysis Transplantation · 2017
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 treatment-emergent 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. SP428 Figure