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, t1/2 (4.56 +/- 2.56) h, Cmax (46.29 +/- 21.07) ng x mL(-1), AUC(0-infinity) (173.76 +/- 87.36) ng x mL(-1) x h. The estimated Kin was (0.41 +/- 0.31)% h(-1), Kout was (0.40 +/- 0.26) h(-1), the IC50 value was (24.40 +/- 21.10) ng x mL(-1) and the area under the effect curve (AUE) was (3.82 +/- 1.46)% h for the indirect response PD model. The Ke0 was (0.35 +/- 0.27) h(-1), the EC50 was (24.30 +/- 24.30) ng x 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.