First-in-human study to investigate the safety and pharmacokinetics of salvianolic acid A and pharmacokinetic simulation using a physiologically based pharmacokinetic model.

Abstract

Salvianolic acid A (SAA) is a water-soluble phenolic acid component from Salvia miltiorrhiza Bunge currently under development for myocardial protection treatment for coronary heart disease (CHD). We investigated the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of SAA. Additionally, a physiologically based pharmacokinetic (PBPK) model was developed to simulate the pharmacokinetics of SAA. This was a first-in-human (FIH), randomized, double-blind, placebo-controlled, single, and multiple-dose study in 116 healthy Chinese subjects with the range of 10-300mg and 60-200mg SAA, respectively. SAA was well tolerated at all dose levels, following both single and multiple doses, with a low overall incidence of treatment-emergent adverse events (TEAEs) which appeared to be no dose-related. The main pharmacokinetic parameter of SAA, assessed by the power model, was the lack of proportionality with the dose range after single dosing. The 90% CIs of the slope β of Cmax (1.214 [1.150-1.278]) and AUC0-t (1.222 [1.156-1.288]) were not within the predefined acceptance range, and the direction of the deviation was higher than expected. PBPK modeling suggested the transfer ability saturation of hepatic organic anion-transporting polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp) might result in a relatively low distribution rate at higher doses. Clinical plasma concentrations observed were in good agreement with PBPK prediction. SAA showed well-characterized pharmacokinetics and was generally well tolerated in the dose range investigated. The PBPK model provides valuable pharmacokinetic knowledge for further clinical development.