Impact of Drug-Gene-Interaction, Drug-Drug-Interaction, and Drug-Drug-Gene-Interaction on (es)Citalopram Therapy: The PharmLines Initiative.

Muh Akbar Bahar,Jens H J Bos,Bob Wilffert,Pauline Lanting,Rolf H Sijmons,Eelko Hak

doi:10.3390/jpm10040256

Abstract

We explored the association between CYP2C19/3A4 mediated drug-gene-interaction (DGI), drug-drug-interaction (DDI) and drug-drug-gene-interaction (DDGI) and (es)citalopram dispensing course. A cohort study was conducted among adult Caucasians from the Lifelines cohort (167,729 participants) and linked dispensing data from the IADB.nl database as part of the PharmLines Initiative. Exposure groups were categorized into (es)citalopram starters with DGI, DDI and DDGI. The primary outcome was drug switching and/or dose adjustment, and the secondary was early discontinuation after the start of (es)citalopram. Logistic regression modeling was applied to estimate adjusted odd ratios with their confidence interval. We identified 316 (es)citalopram starters with complete CYP2C19/3A4 genetic information. The CYP2C19 IM/PM and CYP3A4 NM combination increased risks of switching and/or dose reduction (OR: 2.75, 95% CI: 1.03–7.29). The higher effect size was achieved by the CYP2C19 IM/PM and CYP3A4 IM combination (OR: 4.38, 95% CI: 1.22–15.69). CYP2C19/3A4 mediated DDIs and DDGIs showed trends towards increased risks of switching and/or dose reduction. In conclusion, a DGI involving predicted decreased CYP2C19 function increases the need for (es)citalopram switching and/or dose reduction which might be enhanced by co-presence of predicted decreased CYP3A4 function. For DDI and DDGI, no conclusions can be drawn from the results.

Highlights

Selective serotonin re-uptake inhibitors (SSRIs) such as citalopram and escitalopram ((es)citalopram) are among the first-line pharmacological options for depression in Europe and the US, and the use of SSRIs has increased considerably over the years [1,2]
After looking on the combination of exposures (CYP2C19/3A4 genotypes and Cytochrome P450 (CYP) modulators) among our study population, we found that 9%, 47%, and 8.5% of participants were exposed to DDIs, drug-gene interaction (DGI), and DDGIs, respectively
In this explorative inception cohort study, we presented for both CYP2C19 and CYP3A4 the associations of DGI, DDI, and DDGI and the risk of switching or dose adjustments and early discontinuation in the first treatment episode ofcitalopram

Summary

Introduction

Selective serotonin re-uptake inhibitors (SSRIs) such as citalopram and escitalopram ((es)citalopram) are among the first-line pharmacological options for depression in Europe and the US, and the use of SSRIs has increased considerably over the years [1,2]. Reports showed that less than 50% of (es)citalopram users achieved disease symptom remission during their first treatment episode, and prognosis appeared unpredictable [3,4]. Such variable effectiveness may be explained by a large inter-individual pharmacokinetic variability among patients treated with (es)citalopram [5,6]. Some studies have investigated the role of CYP2C19 and CYP2D6 polymorphisms on the exposure as well as the clinical impact of (es)citalopram [7,10] Such interaction between the drug treatment and genetic variation is referred to as drug-gene interaction (DGI) [11]. The concomitant administration of CYP2C19, CYP3A4, and/or CYP2D6 (CYP2C19/3A4/2D6) modulator drugs (inhibitor/inducer) produces a drug-drug-interaction (DDI) with (es)citalopram by affecting blood concentrations and modifying its effectiveness [12]

Methods

Results

Discussion

Conclusion