Pharmacokinetic-pharmacodynamic modeling of telmisartan using an indirect response model in spontaneously hypertensive rats
Abstract
Aim: To investigate the pharmacokinetic (PK) and the pharmacodynamic (PD) properties of telmisartan in spontaneously hypertensive (SH) rats using an indirect response and effect-compartment link models, and compare two PK-PD models fitting quality.
Methods: The SH rats received a single oral dose of 2, 4, and 8 mg/kg of telmisartan. The plasma concentrations of telmisartan were determined by the liquid chromatography-mass spectrum method. The mean arterial blood pressure was measured to characterize the pharmacodynamics of telmisartan by tail-cuff manometry. The relationship for the telmisartan concentration-hypotensive effect in the SH rats was characterized using an indirect response model.
Results: The PK parameters showed dose proportionality, with a long terminal half-life of 16 h, a clearance of 0.15 L kg-1 h-1, and a volume of distribution of 5.36 L kg-1 in the study. For the indirect response PD model, the estimated Kin were 36.6, 34.1, and 32.8 % h-1, Kout were 36.7, 34.6, and 31.9 h-1; the IC50 values were 86.2, 95.8, and 91.1 ng mL-1; and the area under the effect curve (AUEC) were 762.8, 1490.5, and 2086.2 mmHg h at three doses, respectively. For the effect-compartment model, the Keo were 29.4, 33.8, and 28.7 h-1; the IC50 values were 78.2, 85.7, and 80.9 ng mL-1, and the AUEC were 781.5, 1602.8, and 2215.7 mmHg-hat three doses, respectively.
Conclusion: According to Akaike's information criterion values, the proposed indirect response model provided a more appropriate and good-fitting PK/PD characterization of telmisartan than the effect-compartment link model in SH rats.
Keywords:
Methods: The SH rats received a single oral dose of 2, 4, and 8 mg/kg of telmisartan. The plasma concentrations of telmisartan were determined by the liquid chromatography-mass spectrum method. The mean arterial blood pressure was measured to characterize the pharmacodynamics of telmisartan by tail-cuff manometry. The relationship for the telmisartan concentration-hypotensive effect in the SH rats was characterized using an indirect response model.
Results: The PK parameters showed dose proportionality, with a long terminal half-life of 16 h, a clearance of 0.15 L kg-1 h-1, and a volume of distribution of 5.36 L kg-1 in the study. For the indirect response PD model, the estimated Kin were 36.6, 34.1, and 32.8 % h-1, Kout were 36.7, 34.6, and 31.9 h-1; the IC50 values were 86.2, 95.8, and 91.1 ng mL-1; and the area under the effect curve (AUEC) were 762.8, 1490.5, and 2086.2 mmHg h at three doses, respectively. For the effect-compartment model, the Keo were 29.4, 33.8, and 28.7 h-1; the IC50 values were 78.2, 85.7, and 80.9 ng mL-1, and the AUEC were 781.5, 1602.8, and 2215.7 mmHg-hat three doses, respectively.
Conclusion: According to Akaike's information criterion values, the proposed indirect response model provided a more appropriate and good-fitting PK/PD characterization of telmisartan than the effect-compartment link model in SH rats.