MO020SAFETY, TOLERABILITY, PHARMACOKINETICS (PK), AND PHARMACODYNAMICS (PD) OF SINGLE DOSES OF TAK-272, A NOVEL RENIN INHIBITOR, IN HEALTHY MALE SUBJECTS

Abstract

INTRODUCTION AND AIMS: TAK‐272 is a direct renin inhibitor that showed good bioavailability and strong inhibition of plasma renin activity (PRA) in preclinical studies. This study evaluated the safety and PK/PD of a single oral administration of TAK‐ 272 in healthy male subjects. METHODS: This phase 1 study in healthy Japanese male adults (age: 20‐35 yrs; body mass index: ≥ 18.5 and <25.0 kg/m2) was composed of 2 parts: a Dose‐Ascending Part and a Food Effect Part. The Dose‐Ascending Part (double‐blind, placebo‐controlled, parallel group design) comprised 7 steps: Steps 1‐6 (dose ascending from 10‐400 mg based on review of safety/PK data; Step 6 [400 mg] was not conducted) and Step 8 (5 mg, added based on review of PK/PD data). Each step included 10 distinct subjects (TAK‐272, n=8; placebo, n=2). Blood sampling for PK/PD was performed 1 hr before and up to 168 hrs after study drug administration. The Food Effect Part (n=12 subjects) was a 1‐step (Step 7), open‐label, 2×2 crossover design with a dose of 50 mg. Results under fasted and fed conditions were compared. There were no dietary salt restrictions in either part. Safety was also assessed throughout the study. RESULTS: 72 subjects were randomized and 70 completed the study. There were no obvious differences in demographic and baseline characteristics between the dose groups. The Table shows PK parameters for unchanged TAK‐272 (TAK‐272F). There was a generally linear relationship between dose and either area under the plasma concentration‐time curve (0 to infinity; AUC0‐inf) or maximum plasma concentration (Cmax). The AUC0‐inf of the major metabolite of TAK‐272 was <3% that of TAK‐272F. There was little relationship between plasma concentrations of TAK‐272F and changes from time‐matched baseline in corrected (Fridericia's method) QT intervals (slope for the linear mixed model: ‐0.0010 ms per ng/mL). PRA was rapidly inhibited by TAK‐ 272 at all doses; inhibition lasted up to 24 hrs at all doses and longer with increasing dose. Plasma active renin concentration (PRC) increased, reaching a maximum at approximately 6 hrs; the effect on PRC was nearly dose‐dependent. Regarding the effect of food on PK, the point estimates (90% CI) of the geometric least squares mean ratios (fed/fasted) were 0.950 (0.839‐1.075) for AUC0‐inf and 0.865 (0.697‐1.073) for Cmax; the 90% CI for AUC0‐inf met the bioequivalence criteria (0.80‐1.25). Across both study parts, the number of subjects with treatment‐emergent adverse events (TEAEs) ranged from 0 to 3 per treatment group with no dependency on dose or food intake. All TEAEs except 2 were mild in intensity; only headache and epistaxis occurred in >1 subject (n=2 each). There were no serious AEs or deaths. CONCLUSIONS: A single oral administration of TAK‐272 at doses of 5‐200 mg was safe and well tolerated, with no dose‐limiting toxicity. TAK‐272 was rapidly absorbed. AUC0‐inf and Cmax of TAK‐272F generally showed dose‐proportionality in the range of 5‐200 mg. TAK‐272 administration resulted in rapid inhibition of PRA and increase in PRC. Food had no clinically significant effect on PK or safety.