Pharmacokinetic/pharmacodynamic modelling of venlafaxine: pupillary light reflex as a test system for noradrenergic effects.
OBJECTIVE
Venlafaxine and its major active metabolite O-desmethylvenlafaxine selectively inhibit serotonin and norepinephrine reuptake from the synaptic gap. The inhibition of norepinephrine uptake is assumed to enhance antidepressant efficacy when venlafaxine is given at higher therapeutic doses. Thus investigation of the concentration-response relationship of noradrenergic effects is of clinical interest. We used pupillography as a test system for the pharmacodynamic response to venlafaxine, since it had been shown to be useful for assessment of noradrenergic effects on the autonomous nervous system. The aim of the study was to develop a pharmacokinetic/pharmacodynamic model by means of nonlinear mixed-effects modelling in order to describe the time course of the noradrenergic response to venlafaxine.


METHODS
Twelve healthy male subjects received venlafaxine 37.5 mg or placebo orally twice daily for 7 days and subsequently 75 mg or placebo twice daily for another 7 days. After a 14-day washout phase, the two groups were crossed over. After the last dose of venlafaxine or placebo on day 14, blood samples were drawn to determine venlafaxine and O-desmethylvenlafaxine concentrations and the amplitude and recovery time of the pupillary light reflex were measured. A pharmacokinetic/pharmacodynamic model was developed to describe the data using nonlinear mixed-effects modelling.


RESULTS
The pharmacokinetic part of the model could be simultaneously fitted to both venlafaxine and O-desmethylvenlafaxine data, yielding precise parameter estimates that were similar to published data. The model detected high variability of the intrinsic clearance of venlafaxine (94.8%), most likely due to cytochrome P450 2D6 polymorphism. Rapid development of tolerance of the pupillary light reflex parameters was seen and could be successfully accounted for in the pharmacodynamic part of the model. The half-life of development and regression of tolerance was estimated to be 30 minutes for the amplitude and 40 minutes for the recovery time.


CONCLUSIONS
The time course of the effect and the concentration-response relationship were successfully described by a pharmacokinetic/pharmacodynamic model that takes into account the rapid development of tolerance of pupillary light reflex parameters. This provides a basis for further investigations of the applicability of pupillography as a surrogate measurement of the effectivity of antidepressant drugs with norepinephrine reuptake-inhibiting properties.
Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany. lindauer@uni-bonn.de
Andreas
A
Lindauer
Timo
T
Siepmann
Reinhard
R
Oertel
Angelika
A
Jung
Tjalf
T
Ziemssen
Ulrich
U
Jaehde
Wilhelm
W
Kirch
Martin
M
Siepmann
D018759:Adrenergic Uptake Inhibitors / Q000493:pharmacokinetics*; D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003511:Cyclohexanols / Q000493:pharmacokinetics* / Q000494:pharmacology; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008954:Models, Biological; D009638:Norepinephrine / Q000502:physiology*; D012025:Reflex, Pupillary / Q000187:drug effects*; D000069470:Venlafaxine Hydrochloride
D018759:Adrenergic Uptake Inhibitors; D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D000069470:Venlafaxine Hydrochloride; D009638:Norepinephrine