A pharmacokinetic-pharmacodynamic model incorporating a conditioned response accurately describes the chronotropic effects of cocaine in humans, highlighting the role of conditioning in psychoactive drug responses.
Suggests caution predicting cocaine chronotropy from uniform models; extends PK-PD frameworks to conditioned responses.
We developed a pharmacokinetic-pharmacodynamic model of the heart rate response to cocaine consisting of the sum of the baseline heart rate, a chronotropic drug effect, and a conditioned heart rate response. The conditioned response was modeled as having a monoexponential decline. Cocaine's chronotropic effect was modeled as obeying a maximum (Emax) drug-effect relationship without tachyphylaxis. The model was tested by fitting the kinetic and heart rate data from an earlier study. The data from five subjects in that study were well fit by the model: mean Emax, 64 beats/min, and mean drug concentration producing 50% of Emax, 838 ng cocaine/ml. The data from the other three subjects in that study were fit well, employing a linear rather than an Emax drug effect relationship: mean effect coefficient, 0.035 beats/min/ng cocaine/ml. The findings emphasize the importance of conditioning in the responses to psychoactive drugs.
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Noe et al. (1991) studied this question.
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