Pharmacokinetics and drug interactions: update for new antipsychotics

Advances in our understanding of schizophrenia have led to a new generation of antipsychotic agents. These medications not only demonstrate reduced extrapyramidal symptoms but also possess pharmacologic profiles that can be especially advantageous in treating the negative symptoms of schizophrenia. The pharmacokinetics of many of the newer agents are compared and contrasted with typical neuroleptics. Changes in the pharmacokinetics and dosage of the newer agents are also reviewed. A particular emphasis is placed on the metabolism of the newer agents and their potential for drug-drug pharmacokinetic interactions. Clozapine, the archetypal atypical agent, has a complex pharmacokinetic profile with extremely large interpatient variability and many well-documented drug-drug interactions. Thus, clozapine presents special challenges in dose optimization and requires vigilant clinical monitoring for cardiovascular, neurologic, and hematologic adverse effects. Olanzapine demonstrates a very low potential for drug-drug interactions; it requires extremely high inhibitory concentrations at cytrochrome P450 (CYP) systems, typically 30-fold above the usual concentrations observed at steady-state oral high-dose therapy. The metabolic pathways of olanzapine include N-glucuronidation, reducing its overall sensitivity to drugs that might induce or inhibit its own metabolism via CYP or flavin-containing monooxygenase (FMO) systems. Plasma olanzapine concentrations at steady state typically demonstrate only a fourfold to fivefold variability among patients at a standard dose of medications. Sertindole and risperidone demonstrate polymorphic metabolism characteristics mirroring the CYP 2D6 phenotype. The inhibitory potentials of sertindole at CYP 2D6 and CYP 3A are modest and not likely to be of clinical significance. However, in those patients taking CYP 2D6 inhibitors or in those who are genotypic poor metabolizers, concentrations achieved by sertindole and its metabolites might result in moderate inhibition of CYP 3A.