Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SPH3127: A Phase I, Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE

To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of single- and multiple-dose SPH3127 in healthy individuals.

METHODS

This was a randomized, double-blind, placebo-controlled, Phase I dose-escalation study.

FINDINGS

SPH3127 exposure, expressed as C, AUC, and AUC, was proportionally increased with dose for a range of 25-800 mg (single ascending dose [SAD]) and 100-400 mg daily (multiple ascending doses [MADs]). In an SAD, the C values with 25, 50, 100, 200, 400, and 800 mg of SPH3127 were 90.67, 344.50, 523.50, 1239.50, 2445.00, and 5753.33 ng/mL, respectively. The corresponding AUC values were 294.48, 843.62, 1109.33, 2858.56, 6697.50, and 13057.83 h × ng/mL. In MADs, after the first dose of SPH3127, the C values with 100, 200, and 400 mg of SPH3127 were 421.50, 969.00, and 2468.33 ng/mL, respectively. The corresponding AUC values were 1279.28, 2275.77, and 5934.26 h × ng/mL. At steady state, the C values with 100, 200, and 400 mg of SPH3127 were 514.67, 1419.17, and 2513.33 ng/mL, respectively. The corresponding AUC values were 1638.14, 3096.20, and 7577.70 h × ng/mL. The median T range from 0.33 to 1.0 h and the median t from 3 to 4 h. In an SAD, when the dose was >100 mg, plasma renin activity inhibition of up to 90% lasted up to 24 h. In MADs, renin activity was continuously inhibited by up to 90% in each group for 24 h after the last administration. Treatment-emergent adverse events (AEs) were reported in 29.2% of individuals receiving the SAD and 33.3% of those receiving MADs. Only mild adverse events occurred.

IMPLICATIONS

SPH3127 was well tolerated and had robust and sustained suppression of plasma renin activity. CLINICALTRIALS.

GOV IDENTIFIERS

NCT03128138 (SAD study) and NCT03255993 (MAD study).