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

Abstract

The onset of variant angina (VA) shows circadian rhythmicity that its attacks occur most often from midnight to early morning. Thus, chronotherapeutic treatments should be tailored accordingly to its occurrence frequency. Tanshinol (TS), the bioactive component of Salvia miltiorrhiza was used as the model drug. The pharmacokinetics, pharmacodynamics and PK-PD relationship of TS was investigated in angina model rabbits. The therapeutic effect of TS was evaluated from different aspects including cardiac injury, oxidative stress and vascular endothelium by measuring the serum levels of cTn-I, CK-MB, SOD and NO. In addition, the change of cTn-I levels from baseline as the pharmacodynamic endpoint was used for establishing the pharmacodynamic model. To synchronize the therapeutic effect profile of TS to the occurrence frequency of VA, ideal time courses of therapeutic effect, plasma concentration and drug release were simulated and calculated based on pharmacodynamic/deconvolution integrated model method. Then, sustained release pellets of TS (TS-SRPs) were developed according to the above calculated results and evaluated in vitro-in vivo. The established pharmacodynamic model of TS could precisely quantify the relationship between its effect and concentration. Then, ideal time courses of therapeutic effect, plasma concentration and release of TS were simulated and calculated successfully. After formulation optimization, the prepared TS-SRPs exhibited similar in vitro and in vivo behaviors to the corresponding ideal ones. Meanwhile, the effect curves of TS were synchronous with the occurrence frequency of VA, implying that appropriate therapeutic effect could be provided according to the needs of patients. In conclusion, the tailor of therapeutic effect based on integrated model method is efficient, feasible and reliable.