Pharmacodynamic models for the cardiovascular effects of moxonidine in patients with congestive heart failure

Abstract

Aims: To assess the pharmacodynamics of moxonidine in patients with functional NYHA Class II-III congestive heart failure (CHF).

Methods: A parallel population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed to assess the effect of moxonidine (0.1, 0.2, 0.3 mg twice daily) and placebo treatment on plasma noradrenaline (NA) levels, standing systolic blood pressure (SBP), and heart rate (HR) over 12 weeks in 97 patients with CHF using a parallel group design with dose escalation. A sequential analysis was also developed, where the relative changes in NA concentration were related to both SBP and HR.

Results: In the parallel PD analysis, an effect delay was shown for all three end points (NA, SBP, and HR). An inhibitory Emax model was used to characterize the concentration-effect relationships. For SBP and HR, the EC50 value increased over time. For NA, there was a positive baseline drift over the 12 weeks; this was interpreted as disease progression. Moxonidine delayed this increase by 9.8 weeks. For SBP, there was a circadian pattern at baseline. In the sequential PD analysis, the relationship between the drug response (NA) and SBP or HR was best described by an inhibitory Emax model. No effect delays between the response and effects were found.

Conclusions: Effects of moxonidine on NA, SBP, and HR could be quantified by an effect compartment model in the presence of disease progression and circadian variations. Disease progression, as judged by increasing NA levels with time, was delayed by moxonidine. A direct relationship was found between NA and SBP/HR.

Figure 1

The change in noradrenaline concentrations relative to baseline for placebo (▪) and divided total daily moxonidine doses of 0.2 mg (□), 0.4 mg (▴), and 0.6 mg (▵) vs time (mean ± 2 s.e. mean) observed at start of treatment (week 0), after 2 weeks maintenance dose (week 4), and after additional 8 weeks steady state treatment (week 12).

Figure 2

The change in blood pressure relative to baseline for placebo (▪) and divided total daily moxonidine doses of 0.2 mg (□), 0.4 mg (▴), and 0.6 mg moxonidine (▵) vs time (mean ± 2 s.e.mean) observed at start of treatment (week 0), after each dose escalation (week 1 and 2), and during steady state (week 4, 8, and 12).

Figure 3

The change in heart rate relative to baseline for placebo (▪) and divided total daily moxonidine doses of 0.2 mg (□), 0.4 mg (▴), and 0.6 mg (▵) moxonidine vs time (mean ± 2 s.e.mean) observed at start of treatment (week 0), after each dose escalation (week 1 and 2), and during steady state (week 4, 8, and 12).

Figure 4

Basic goodness of fit plots for the final parallel analysis (full data set) of noradrenaline (left panel), standing systolic blood pressure (middle panel), and heart rate (right panel) model, respectively. All plots shows the predictions based on population parameter estimates (PRED) and individual parameter estimates (IPRED) vs the observed effects (DV). The solid diagonal lines are the lines of identity.