Highlights
- •This is a randomized, double-blind, placebo-controlled, phase 1 study.
- •SPH3127 was safe and well-tolerated.
- •SPH3127 had strong and sustained suppression of plasma renin activity.
Abstract
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 Cmax, AUC0–t, and AUC0–∞, 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
Cmax 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 AUC0–t 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 Cmax values with 100, 200, and 400 mg of SPH3127 were 421.50, 969.00, and 2468.33 ng/mL,
respectively. The corresponding AUC0–t values were 1279.28, 2275.77, and 5934.26 h × ng/mL. At steady state, the Cmax values with 100, 200, and 400 mg of SPH3127 were 514.67, 1419.17, and 2513.33 ng/mL,
respectively. The corresponding AUC0–24 values were 1638.14, 3096.20, and 7577.70 h × ng/mL. The median Tmax range from 0.33 to 1.0 h and the median t1/2 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).
Key words
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References
- Physiology, renin angiotensin system.in: StatPearls. Treasure Island (FL). 2019
- The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report.JAMA. 2003; 289: 2560-2572https://doi.org/10.1001/jama.289.19.2560
- Advances in understanding the renin-angiotensin-aldosterone system (RAAS) in blood pressure control and recent pivotal trials of RAAS blockade in heart failure and diabetic nephropathy.F1000 Res. 2017; 6 (Faculty Review–297)https://doi.org/10.12688/f1000research.9692.1
- Inappropriate activity of local renin-angiotensin-aldosterone system during high salt intake: impact on the cardio-renal axis.Braz J Nephrol. 2018; 40: 170-178https://doi.org/10.1590/2175-8239-JBN-3661
- Aliskiren--an orally active renin inhibitor. Review of pharmacology, pharmacodynamics, kinetics, and clinical potential in the treatment of hypertension.Vasc Health Risk Manag. 2007; 3: 809-815
- Evaluation of preclinical safety profile of SPH3127, a direct renin inhibitor, after 28-day repeated oral administration in Sprague-Dawley rats and cynomolgus monkeys.Regul Toxicol Pharmacol. 2019; 109: 104484https://doi.org/10.1016/j.yrtph.2019.104484
- The Nonclinical pharmacokinetics and prediction of human pharmacokinetics of SPH3127, a novel direct renin inhibitor.Eur J Drug Metab Pharmacokinet. 2020; 45: 15-26https://doi.org/10.1007/s13318-019-00573-9
- World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.JAMA. 2013; 310: 2191-2194https://doi.org/10.1001/jama.2013.281053
- ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R1). 1996
- Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (07/05/2005).2005
- Guideline on Strategies to Identify and Mitigate Risks for First-In-Human and Early Clinical Trials with Investigational Medicinal Products.European Medicines Agency, London2007
- Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.State Food and Drug Administration notes [2012] No. 122, 2012
- China FDA Technical Guidelines on Clinical Pharmacokinetic Research of Chemical Drugs. 2005
Article info
Publication history
Published online: February 27, 2021
Accepted:
January 26,
2021
Identification
Copyright
© 2021 Elsevier Inc.
