L. Brynne et al., Pharmacodynamic models for the cardiovascular effects of moxonidine in patients with congestive heart failure, BR J CL PH, 51(1), 2001, pp. 35-43
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.