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

Abstract

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.