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Vol. 302, Issue 3, 1158-1167, September 2002
Division of Pharmacology, Leiden/Amsterdam Center for Drug
Research, Leiden University, Leiden, The Netherlands (S.A.G.V.,
C.J.G.M.S., B.P.R.R., M.D.); Pfizer Global Research & Development,
Discovery Biology, Sandwich, Kent, United Kingdom (P.H.v.d.G.);
Mathematical Institute, Leiden University, Leiden, The Netherlands
(L.A.P.)
The neuroactive steroid alphaxalone reveals a complex biphasic
concentration-effect relationship using the 11.5 to 30 Hz frequency band of the electroencephalogram (EEG) as biomarker. The purpose of the
present investigation was to develop a mechanism-based pharmacokinetic-pharmacodynamic model to describe this observation. The
proposed model is based on receptor theory and aims to separate the
drug-receptor interaction from the transduction of the initial stimulus
into the observed biphasic response. Individual concentration-time courses of alphaxalone were obtained in combination with continuous recording of the EEG parameter. Alphaxalone was administered
intravenously in various dosages. The pharmacokinetics were described
by a two-compartment model, and parameter estimates for clearance,
intercompartmental clearance, volume of distribution 1 and 2 were
158 ± 29 ml · min
1 · kg1, 143 ± 31 ml · min1
· kg1, 122 ± 20 ml · kg1 and
606 ± 48 ml · kg1, respectively.
Concentration-effect relationships exhibited a biphasic pattern and
delay in onset of effect. The hysteresis was described on the basis of
an effect-compartment model with Cmax as
covariate. The pharmacodynamic model consisted of a receptor model,
featuring a monophasic saturable receptor activation model in
combination with a biphasic stimulus-response model. The in vivo
affinity (KPD) was estimated at 432 ± 26 ng · ml1. Unique parameter estimates were
obtained that were independent of the dose and the duration of the
infusion. In conclusion, we have shown that this mechanism-based
approach, which separates drug- and system-related properties in vivo,
was successfully applied for the characterization of the biphasic
effect versus time patterns of alphaxalone. The model should be of use
in the characterization of other biphasic responses.
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