Drug metabolism as a confounding factor in PK/PD population approaches

Pharmacokinetic/pharmacodynamic population approaches aim at establishing relationships between dose, drug concentration of active principles and clinical response, accounting for factors responsible for inter-individual variability. Additional difficulties in the presence of metabolites include the need to decide a priori which metabolites should be monitored according to their respective role in efficacy and/or toxicity, the need to select appropriate selective analytical methods, and the requirement for more complex pharmacokinetic and/or pharmacodynamic models. These points are discussed more extensively for psychotropic drugs, and in particular for the active metabolites of phenothiazines, for reduced haloperidol, for the desmethylated and hydroxylated metabolites of tricyclic antidepressants, and for the desmethyl metabolites of the serotonin-specific reuptake inhibitors fluoxetine and citalopram.