Population pharmacokinetic-pharmacodynamic model of craving in an enforcedsmoking cessation population: Indirect response and probabilistic modeling

Purpose. A population pharmacokinetic-pharmacodynamic model accounting for placebo effect was used to relate nicotine concentration and enforced smoki ng cessation craving score measured by the Tiffany rating scale short form. Methods. Twenty-four smokers were enrolled in a placebo-controlled, randomi zed, double-blind, three periods, crossover trial. The study objective was to describe the nicotine-induced changes on craving scores. Two modeling st rategies based on a mechanistic (indirect response models with drug-related inhibition on the k(in) synthesis rate and with a drug-related stimulation of the k(out) removal rate were evaluated) and a probabilistic (logistic r egression) approach were used. Results. Placebo response model properly fitted the circadian changes on cr aving scores. The analysis revealed that the indirect response model with i nhibition on k(in) was the preferred model for the smoking data whereas the preferred model for the Nicotine Replacement Therapy data was the one with stimulation on k(out). The logistic analysis showed that the nicotine conc entration was a significant predictor of reduction in craving during the fr ee-smoking period. Conclusions. Nicotine dosage regimen can influence the nicotine mechanism o f action: an instantaneous delivery at an individually selected time seems to inhibit the onset of craving while constant delivery at a pre-defined ti me seems to attenuate the craving.