Pharmacokinetic-pharmacodynamic modeling of telmisartan using an indirect response model in spontaneously hypertensive rats.
OBJECTIVE
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 Lxkg( -1) xh( -1), and a volume of distribution of 5.36 Lxkg( -1) in the study. For the indirect response PD model, the estimated K(in) were 36.6, 34.1, and 32.8 %.h( -1), K(out) were 36.7, 34.6, and 31.9 h( -1); the IC(50) values were 86.2, 95.8, and 91.1 ngxmL( -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 K(eo) were 29.4, 33.8, and 28.7 h( -1); the IC(50) values were 78.2, 85.7, and 80.9 ngxmL(-1), and the AUEC were 781.5, 1602.8, and 2215.7 mmHg.h at three doses, respectively.


CONCLUSIONS
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.
Hao
Kun
K
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Chen
Yuan-Cheng
YC
Cao
Yan-Guang
YG
Yu
Dan
D
Liu
Xiao-Quan
XQ
Wang
Guang-Ji
GJ
D047228:Angiotensin II Type 1 Receptor Blockers / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D001565:Benzoates / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D008954:Models, Biological; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D000077333:Telmisartan