Effect of smoking on risperidone pharmacokinetics - A multifactorial approach to better predict the influence on drug metabolism

Purpose: To disentangle an association between tobacco smoking, smoking habits and pharmacokinetic patterns such as plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety, AM, (RIS + 9-OH-RIS) in a naturalistic sample. Methods: Plasma concentrations, dose adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS and AM in patients out of a therapeutic drug monitoring (TDM) database were compared between smokers (n = 401) and nonsmokers (n = 292). Results: Daily dosage of risperidone differed significantly with smokers receiving higher doses than patients in the control group (p = 0.001). No differences were detected in plasma concentrations of the active moiety, RIS and 9-OH-RIS (p = 0.8 for AM, p = 0.646 for RIS and p = 0538 for 9-OH-RIS). However, dose corrected concentrations (C/D) of metabolite (C/D 9-OH-RIS) and active moiety (C/D AM) differed between significantly between groups (p = 0.002 and p = 0.007). After stratifying smokers to a group of moderate smokers (<20 cigarettes/clay) (RS1, n = 109) and a group of heavy smokers (>= 20 cigarettes clay) (RS2, n = 135), the comparison between non-smokers and both groups only showed lower values of C/D for 9-OH-RIS (p = 0.011) for the group of moderate smokers while other pharmacokinetic parameters did not differ. Conclusions: Apart from the well-known induction of CYP1A2 activity by polycyclic aromatic hydrocarbons, smoking might exert an effect on other CYP isoenzymes as well. A possible interpretation proposes a slight inducing effect of smoking on rispericlone metabolism most likely via CYP3A4. (C) 2016 Elsevier B.V. All rights reserved.