Key result
Irbesartan plus HCTZ demonstrated synergistic blood pressure lowering action compared to irbesartan alone in renal hypertensive dogs, with irbesartan increasing the peak plasma concentration of HCTZ.
Why the study?
Does the combination of irbesartan and hydrochlorothiazide improve blood pressure lowering and alter pharmacokinetics compared to monotherapy in renal hypertensive dogs?
Does the combination of irbesartan and hydrochlorothiazide improve blood pressure lowering and alter pharmacokinetics compared to monotherapy in renal hypertensive dogs?
The combination of irbesartan and hydrochlorothiazide demonstrates a synergistic pharmacodynamic interaction for blood pressure lowering in a renal hypertensive dog model.
Should not change clinical practice; leaves open translation of synergistic BP lowering from renal hypertensive dogs to humans.
Combined irbesartan/hydrochlorothiazide (HCTZ) formulations are often used clinically. Pharmacokinetic-pharmacodynamic (PK/PD) modeling was applied to investigate the pharmacokinetic and pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs at non-steady-state and steady-state. The renal hypertensive dogs were treated with oral irbesartan alone, or HCTZ alone, or the combination of irbesartan and HCTZ for 8 days. Blood pressure and plasma concentrations were measured and pharmacokinetic-pharmacodynamic parameters were analyzed. Irbesartan showed a two-compartment model pharmacokinetic profile. The concentration-time course of irbesartan was not changed by HCTZ, but irbesartan increased the peak plasma concentration and area under the curve of HCTZ at steady-state. HCTZ had no blood pressure lowering effect at non-steady-state. Irbesartan plus HCTZ had greater blood pressure lowering action than irbesartan alone. HCTZ increased actions of irbesartan. Hysteresis loops were found between effect and plasma concentrations of irbesartan after a single dose. However, hysteresis loops disappeared at steady state with more rapid realization of maximum concentration and effects. The relationship between effects and effect-compartment concentrations of the drugs was represented by a sigmoid Emax model. The results suggest synergistic pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs and some differences of pharmacokinetic-pharmacodynamic properties between irbesartan and irbesartan/HCTZ combinations at non-steady-state and steady state.
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Huang et al. (2005) studied Renal hypertension. Irbesartan and hydrochlorothiazide (HCTZ) combination vs. Irbesartan alone or HCTZ alone was evaluated on Blood pressure and plasma concentrations. Irbesartan plus HCTZ demonstrated synergistic blood pressure lowering action compared to irbesartan alone in renal hypertensive dogs, with irbesartan increasing the peak plasma concentration of HCTZ.
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