Tailoring therapeutic effect for chronotherapy of variant angina based on pharmacodynamic/deconvolution integrated...

Area of Science:

• Pharmacology
• Chronobiology
• Drug Delivery Systems

Background:

• Variant angina (VA) exhibits circadian rhythmicity, with attacks peaking from midnight to early morning.
• Current chronotherapeutic strategies require optimization to align with VA's occurrence patterns.
• Tanshinol (TS), a Salvia miltiorrhiza component, was selected as a model drug for chronotherapy investigation.

Purpose of the Study:

• To investigate the pharmacokinetics, pharmacodynamics, and PK-PD relationship of Tanshinol (TS) in a rabbit model of angina.
• To develop and evaluate TS sustained-release pellets (TS-SRPs) synchronized with the circadian rhythm of VA attacks.
• To establish an integrated model for tailoring TS therapeutic effects to individual patient needs.

Main Methods:

• Pharmacokinetic and pharmacodynamic studies of TS in angina model rabbits.
• Evaluation of cardiac injury (cTn-I, CK-MB), oxidative stress (SOD), and vascular endothelium function (NO).
• Development and in vitro-in vivo evaluation of TS sustained-release pellets (TS-SRPs) using an integrated pharmacodynamic/deconvolution model.

Main Results:

• A precise pharmacodynamic model quantifying the TS effect-concentration relationship was established.
• Ideal time courses for TS therapeutic effect, plasma concentration, and drug release were successfully simulated.
• Optimized TS-SRPs demonstrated in vitro and in vivo profiles matching ideal simulations, synchronizing therapeutic effects with VA occurrence.

Conclusions:

• The integrated model-based approach enables efficient, feasible, and reliable tailoring of therapeutic effects.
• TS-SRPs offer synchronized therapeutic effects, providing appropriate treatment aligned with VA patient needs.
• This chronotherapeutic strategy holds promise for improving variant angina management.