Pharmacokinetic-pharmacodynamic model for perindoprilat regional haemodynamic effects in healthy volunteers and in congestive heart failure patients

Abstract

Aims: We compared the relationships between the plasma concentrations (C) of perindoprilat, active metabolite of the angiotensin I-converting enzyme inhibitor (ACEI) perindopril, and the effects (E) induced on plasma converting enzyme activity (PCEA) and brachial vascular resistance (BVR) in healthy volunteers (HV) and in congestive heart failure (CHF) patients after single oral doses of perindopril.

Methods: Six HV received three doses of perindopril (4, 8, 16 mg) in a placebo-controlled, randomized, double-blind, crossover study whereas 10 CHF patients received one dose (4 mg) in an open study. Each variable was determined before and 6-12 times after drug intake. E (% variations from baseline) were individually related to C (ng ml(-1)) by the Hill model E=Emax x Cgamma/(CE50gamma + Cgamma). When data showed a hysteresis loop, an effect compartment was used.

Results: (means+/-s.d.) In HV, relationships between C and E were direct whereas in CHF patients, they showed hysteresis loops with optimal k(e0) values of 0.13 +/- 0.16 and 0.13 +/- 0.07 h(-1) for PCEA and BVR, respectively. For PCEA, with Emax set to -100%, CE50 = 1.87 +/- 0.60 and 1.36 +/- 1.33 ng ml(-1) (P = 0.34) and gamma = 0.90 +/- 0.13 and 1.11 +/- 0.47 (P = 0.23) in HV and CHF patients, respectively. For BVR, Emax= -41 +/- 14% and -60 +/- 7% (P = 0.02), CE50 = 4.95 +/- 2.62 and 1.38 +/- 0.85 ng ml(-1) (P = 0.02), and gamma = 2.25 +/- 1.54 and 3.06 +/- 1.37 (P = 0.32) in HV and CHF patients, respectively.

Conclusions: Whereas concentration-effect relationships were similar in HV and CHF patients for PCEA blockade, they strongly differed for regional haemodynamics. This result probably expresses the different involvements, in HV and CHF patients, of angiotensinergic and nonangiotensinergic mechanisms in the haemodynamic effects of ACEIs.

Figure 1

Perindoprilat plasma converting enzyme activity (PCEA) blockade concentration-effect relationship in healthy volunteers (HV, solid line) and in congestive heart failure (CHF, dotted line) patients. The models have the following parameters: E_max=−100%, CE₅₀ = 1.87 ng ml⁻¹, γ= 0.90, and E₀ = 0 in HV, and E_max=−100%, CE₅₀ = 1.36 ng ml⁻¹, γ=1.11, and E₀ = 0 in CHF patients.

Figure 2

Perindoprilat brachial vascular resistance (BVR) decrease concentration-effect relationship in healthy volunteers (HV, solid line) and in congestive heart failure (CHF, dotted line) patients. The models have the following parameters: E_max=−41%, CE₅₀ = 4.95 ng ml⁻¹, γ= 2.25, and E₀ = 0 in HV, and E_max=−60%, CE₅₀ = 1.38 ng ml⁻¹, γ= 3.06, and E₀ = 0 in CHF patients.