Pharmacokinetics and tolerability of atomoxetine in adults of known CYP2D6 phenotype

Abstract

Background/Aims This study was designed to evaluate atomoxetine pharmacokinetics, dose proportionality, and safety in CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) subjects after single dose and at steady state. Methods Part A: single-blind, placebo-controlled, single-dose escalation design from 10 to 120 mg. Part B: single-blind, placebo-controlled, multiple-dose design of 40 mg BID for 7 days. The pharmacokinetics of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine were evaluated using noncompartmental analysis. Safety assessments included adverse events, heart rate (HR), blood pressure (BP), and orthostatic measures. Results Dose proportionality and linearity were shown in both EM and PM. PM had a 10-fold lower clearance and a longer t1/2 than EM subjects (5.23 hr vs. 24.4 hr). HR increases were similar for EM and PM in Part A, while PMs had a maximum HR about 10 bpm higher than EMs in Part B. Conclusions Atomoxetine pharmacokinetics were influenced by the CYP2D6 polymorphism. Orthostatic changes in systolic BP and HR were not clinically significant. The hemodynamic response to atomoxetine was similar across subjects, despite marked differences in exposure due to CYP2D6 polymorphism. EM and PM subjects had similar drug-related adverse event profiles, therefore no dose adjustment is necessary. Clinical Pharmacology & Therapeutics (2005) 77, P27–P27; doi: 10.1016/j.clpt.2004.11.103