Establishment of PK-PD Binding Model for Multi-Components of Crossbow Medicine Microemulsion Based on a Rat Model of Knee Osteoarthritis

OBJECTIVE To establish a combined pharmacokinetic (PK)-pharmacodynamic (PD) model for knee osteoarthritis (KOA) of crossbow drug microemulsion multi-components (benzoylmesaconine, benzoylhypacoitine, mesaconitine, periplocin, neochlorogenic acid, vanillic acid, chlorogenic acid), and elucidate the dynamic changes in the KOA rats and the interrelation with the elapsed efficacy of the drug.

METHODS A KOA rat model was induced by 4% papain; the PK process of crossbow medicine microemulsion components in rat synovial fluid was analyzed by UPLC to establish a PK model; the contents of MMP-3, MMP-13, TNF-α and IL-1β in KOA rats at different time points after administration were determined by ELISA analysis to establish a PD model; Phoenix WinNonlin software was used to fit the PK and PD data to obtain a PK-PD model.

RESULTS PK results showed that the multi-components of the microemulsion were slowly absorbed in the joint cavity and gradually reached the peak value within 3-5 h. The Cmax of benzoylmesaconine, benzoylhypacoitine mesaconitine, periplocoside, neochlorogenic acid, vanillic acid and chlorogenic acid were 1.23, 1.48, 1.62, 4.67, 0.93, 1.25 and 2.35 μg·mL^-1, respectively; the area under the drug-time curve (AUC_0-11) was 2.58, 4.04, 3.54, 12.15, 2.51, 2.41 and 4.11 h·μg·mL^-1, respectively. PD results showed that at different time points after administration, the contents of MMP-3, IL-1β, TNF-α, and MMP-13 decreased to varying degrees, among which MMP-3 decreased insignificantly, with significant differences only at 6 h; the contents of the remaining IL-1β, TNF-α, and MMP-13 decreased significantly (P < 0.05, P < 0.01), and showed the phenomenon of lagged efficacy; the PK-PD binding model showed that the drug concentration of the multi-component drug in the crossbow medicine microemulsion could be well fitted with its drug efficacy data.

CONCLUSION The established PK-PD binding model can predict the drug efficacy changes after administration, and provides a corresponding reference for the crossbow medicine microemulsion treatment of KOA.