Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic ana
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PHARMACOEPIDEMIOLOGY AND PRESCRIPTION
Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic analysis Milo Gatti 1
&
Emanuel Raschi 1
&
Fabrizio De Ponti 1
Received: 15 July 2020 / Accepted: 1 September 2020 # The Author(s) 2020
Abstract Purpose To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents. Methods We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different “SS reporting zones” were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (VD), and lipophilicity) and PD (values of binding affinity (Ki) and IC50 for serotonin reuptake transporter (SERT) and 5-HT2A) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index). Results Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large VD (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for VD/Ki SERT ratio (p = 0.05). Discussion Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis. Keywords Linezolid . Serotonin syndrome . Drug-drug interactions . Pharmacovigilance-pharmacokinetic/pharmacodynamic approach . Infectious disease “dilemma”
Introduction Linezolid is an oxazolidinone antibiotic with activity against multidrug-resistant Gram-positive organisms [1], showing lipophilic features, excellent tissue penetration including the central nervous system (CNS), and weak reversible non-selective Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-020-02990-1) contains supplementary material, which is available to authorized users. * Milo Gatti [email protected] 1
Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio, 48, 40126 Bologna, Italy
monoamine oxidase (MAO) inhibitory effects at therapeutic serum concentrations (according to an inhibitory binding affinity constant (Ki) of 56 μM and
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