A pharmacokinetic–pharmacodynamic model was developed to describe the time course of blood pressure and plasma potassium after long-term telmisartan and/or hydrochlorothiazide administration in spontaneously hypertensive rats. The spontaneously hypertensive rats were administered once daily for 6 weeks. The drug concentration, blood pressure and plasma potassium were monitored for several points. The time courses of blood pressure and plasma potassium were described by indirect response pharmacokinetic–pharmacodynamic model. The synergistic antihypertensive pharmacodynamic interaction between telmisartan and hydrochlorothiazide was observed, which was simulated by the inhibitory function of telmisartan and stimulatory function of hydrochlorothiazide after co-administration of the two drugs. For plasma potassium, when hydrochlorothiazide administrated alone, the plasma potassium reached to a low steady-state level at 4.64 mmol/L for 6 weeks. The plasma potassium increased to a steady-state level at 4.84 mmol/L after co-administration of telmisartan. The time courses of plasma potassium were successfully characterized by indirect response pharmacokinetic–pharmacodynamic model after long-term administration of telmisartan and/or hydrochlorothiazide. The model captured turnovers of blood pressure and plasma potassium in the different time phases and dose conditions.