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

Aims To assess the pharmacodynamics of moxonidine in patients with function al NYHA Class II-III congestive heart failure (CHF). Methods A parallel population pharmacokinetic/pharmacodynamic (PK/PD) analy sis was performed to assess the effect of moxonidine (0.1, 0.2, 0.3 mg twic e daily) and placebo treatment on plasma noradrenaline (NA) levels, standin g systolic blood pressure (SBP), and heart rate (HR) over 12 weeks in 97 pa tients with CHF using a parallel group design with dose escalation. A seque ntial analysis was also developed, where the relative changes in NA concent ration were related to both SEP and HR. Results In the parallel PD analysis, an effect delay was shown for all thre e end points (NA, SEP, and HR). An inhibitory E-max model was used to chara cterize the concentration-effect relationships. For SEP and HR, the EC50 va lue increased over time. For NA, there was a positive baseline drift over t he 12 weeks; this was interpreted as disease progression. Moxonidine delaye d this increase by 9.8 weeks. For SEP, there was a circadian pattern at bas eline. In the sequential PD analysis, the relationship between the drug res ponse (NA) and SEP or HR was best described by an inhibitory E-max model. N o effect delays between the response and effects were found. Conclusions Effects of moxonidine on NA, SEP, and HR could be quantified by an effect compartment model in the presence of disease progression and cir cadian variations. Disease progression, as judged by increasing NA levels w ith time, was delayed by moxonidine. A direct relationship was found betwee n NA and SBP/HR.