Pharmacokinetic-pharmacodynamic relationships of central nervous system effects of XXXX in healthy subjects.

@entity1 @entity303 @entity1726 @entity5591 @entity2414
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:     The cholinergic system is important for different central nervous system functions, including memory, learning and attention. @entity5591 , a centrally active muscarinic antagonist, has been used to model @entity303 and to demonstrate the pharmacological effects of cholinergic drugs, but for most effects the concentration-effect relationships are unknown. WHAT THIS STUDY ADDS:     We determined the pharmacokinetic-pharmacodynamic relationships of @entity5591 using a multidimensional central nervous system test battery in a large group of healthy volunteers. The results suggested there are various functional cholinergic systems with different pharmacological characteristics, which can be used to study the effects of drugs that directly or indirectly modify cholinergic systems. The design of such studies should take the different concentration-effect relationships into account. AIM(S) Although @entity5591 is a frequently used @entity2414 model, the relationships between exposure and corresponding central nervous system (CNS) effects are mostly unknown. The aim of our study was to characterize these using pharmacokinetic-pharmacodynamic (PK- @entity1726 ) modelling. METHODS: In two double-blind, placebo-controlled, four-way crossover studies, 0.5-mg @entity5591 was administered i.v. to 90 healthy male subjects. PK and @entity1726 /safety measures were monitored pre-dose and up to 8.5 h after administration. PK- @entity1726 relationships were modelled using non-linear mixed-effect modelling. RESULTS: Most @entity1726 responses following @entity5591 administration in 85 subjects differed significantly from placebo. As @entity1726 measures lagged behind the plasma PK profile, PK- @entity1726 relationships were modelled using an effect compartment and arbitrarily categorized according to their equilibration half-lives (t(1/2) k(eo) ; hysteresis measure). t(1/2) k(eo) for heart rate was 17 min, saccadic eye movements and adaptive tracking 1-1.5 h, body sway, smooth pursuit, visual analogue scales alertness and psychedelic 2.5-3.5 h, pupil size, finger tapping and visual analogue scales feeling high more than 8 h. CONCLUSIONS: @entity5591 affected different CNS functions in a concentration-dependent manner, which based on their distinct PK- @entity1726 characteristics seemed to reflect multiple distinct functional pathways of the cholinergic system. All @entity1726 effects showed considerable albeit variable delays compared with plasma concentrations. The t(1/2) k(eo) of the central effects was longer than of the peripheral effects on heart rate, which at least partly reflects the long CNS retention of @entity5591 , but possibly also the triggering of independent secondary mechanisms. PK- @entity1726 analysis can optimize @entity5591 administration regimens for future research and give insight into the physiology and pharmacology of @entity1 cholinergic systems.
