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Mirtazapine in combination with amitriptyline: a drug–drug interaction study in healthy subjects
Author(s) -
Sennef C.,
Timmer C. J.,
Sitsen J. M. A.
Publication year - 2003
Publication title -
human psychopharmacology: clinical and experimental
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.461
H-Index - 78
eISSN - 1099-1077
pISSN - 0885-6222
DOI - 10.1002/hup.441
Subject(s) - amitriptyline , mirtazapine , pharmacokinetics , tolerability , placebo , medicine , pharmacodynamics , pharmacology , drug , mianserin , drug interaction , antidepressant , anesthesia , adverse effect , alternative medicine , pathology , hippocampus
Objective To assess the steady‐state pharmacokinetics of mirtazapine (30 mg/day orally) and amitriptyline (75 mg/day orally) during combined administration compared with that of either drug administered alone. To evaluate the tolerability and effects on psychometric tests of acute and subchronic administration of both drugs combined and alone. Methods In a single‐blind, three‐way cross‐over study, 24 (12 male and 12 female) healthy subjects were randomly assigned to six different sequences of three 9‐day treatments, i.e. racemic mirtazapine (30 mg/day), amitriptyline (75 mg/day) or the combination of these drugs. To control for acute pharmacodynamic assessments, during the first treatment period, a placebo group ( n = 8; 4 females and 4 males) was added. Serial blood samples were drawn for plasma level measurements that were subsequently subjected to pharmacokinetic analysis. Psychometric tests assessed attentional performance, and a computer‐assisted telephone questionnaire assessed self‐ratings of drowsiness/alertness and sleep quality. Results Amitriptyline increased the C max of mirtazapine (+ 36%, p < 0.05) in male subjects only. Mirtazapine altered the C max of amitriptyline in both male (+ 23%, p < 0.05) and female (− 23%, p < 0.05) subjects. No changes were observed for other pharmacokinetic parameters. Metabolite parameters were not affected. Changes in parent compound levels mainly resulted from effects on absorption. The psychometric test results did not reveal significant changes between combined and single drug treatments. The telephone registrations of VAMRS and LSEQ did not show clinically relevant differences between the active treatments. Conclusion Combined administration of mirtazapine (30 mg/day) and amitriptyline (75 mg/day) alters the pharmacokinetics of either compound to a minor extent. Adding one drug to the other and substituting one drug by the other had no major effects on tolerability. Nevertheless, caution is warranted when combining amitriptyline and mirtazapine. Copyright © 2003 John Wiley & Sons, Ltd.