Comparison of different pharmacodynamic models for pharmacokinetic-pharmacodynamic (PK-PD) modeling of carvedilol

The paper is aimed to investigate the pharmacokinetic (PK) and the pharmacodynamic (PD)  properties of carvedilol using indirect response and effect-compartment link models, and compare the fitness of PK-PD models.  Twenty male healthy Chinese volunteers received a single oral dose of 20 mg of carvedilol.  The plasma concentrations of carvedilol were determined by reversed-phase HPLC method with fluorescence detection, and the pharmacokinetic parameters were calculated by DAS2.0.  The mean arterial blood pressure was measured and the pharmacodynamics of carvedilol was characterized by tail-cuff manometry.  The main pharmacokinetic parameters of carvedilol were as follows, t_1/2 (4.56 ± 2.56) h, C_max (46.29 ± 21.07) ng·mL^-1, AUC_0-∞ (173.76 ± 87.36) ng·mL^-1·h.  The estimated K_in was (0.41 ± 0.31) % h^-1, K_out was (0.40 ± 0.26) h^-1, the IC₅₀ value was (24.40 ± 21.10) ng·mL^-1 and the area under the effect curve (AUE) was (3.82 ± 1.46) % h for the indirect response PD model.  The K_e0 was (0.35 ± 0.27) h^-1, the EC₅₀ was (24.30 ± 24.30) ng·mL^-1, and the AUE was (5.65 ± 2.54) % h for the effect-compartment model.  The HPLC method can be used for the pharmacokinetic study of carvedilol.  The proposed effect-compartment link model provided more appropriate and better-fitting PK/PD characteristics than the indirect response model in Chinese healthy volunteers according to Akaike’s   information criterion values.