Pharmacokinetic-pharmacodynamic modeling of the effect of fluvoxamine on p-chloroamphetamine-induced behavior

Leiden University, Leyden, South Holland, Netherlands
European Journal of Pharmaceutical Sciences (Impact Factor: 3.35). 11/2007; 32(3):200-8. DOI: 10.1016/j.ejps.2007.07.004
Source: PubMed


The pharmacokinetic-pharmacodynamic (PK-PD) correlation of the effect of fluvoxamine on para-chloroamphetamine (PCA)-induced behavior was determined in the rat. Rats (n=66) with permanent arterial and venous cannulas received a 30-min intravenous infusion of 1.0, 3.7 or 7.3 mg kg(-1) fluvoxamine. At various time points after the start of fluvoxamine administration, a single dose of PCA (2.5 mg kg(-1)) was injected in the tail vein and resulting behavioral effects, excitation (EXC), flat body posture (FBP) and forepaw trampling (FT), were immediately scored (scores: 0, 1, 2 or 3) over a period of 5 min. In each individual animal the time course of the fluvoxamine plasma concentration was determined up to the time of PCA administration. Observed behavioral effects were related to fluvoxamine plasma concentrations. Fluvoxamine pharmacokinetics was described by a population three-compartment pharmacokinetic model. The effects of fluvoxamine on PCA-induced behavior (probability of EXC, FBP and FT) were directly related to fluvoxamine plasma concentration on the basis of the proportional odds model. For EXC, EC(50) values for the cumulative probabilities P(Y<1), P(Y<2), P(Y<3) were 237+/-39, 174+/-28 and 100+/-20 ng ml(-1), respectively. Slightly higher EC(50) values were obtained for the corresponding effects on FBP and FT. This investigation demonstrates the feasibility of PK-PD modeling of categorical drug effects in animal behavioral pharmacology. This constitutes a basis for the future development of a mechanism-based PK-PD model for fluvoxamine in this paradigm.

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    • "One may consider a dose fractionation approach or altered dosing regimen help to define the pharmacokinetics needed to achieve the endpoint. Modeling behavioral pharmacology of psychotropic drugs is often complicated by the fact that non-continuous pharmacodynamic endpoints are reported on a categorical scale (Geldof et al., 2007). Proportional odds models have been successfully applied to data from analgesic trials in which severity of pain, albeit a "
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