Pharmacokinetic Drug Interactions Involving Vortio

Authors: Grace Chen Ronald Lee AstridMaria Højer Jeppe Klint Buchbjerg Michael Serenko Zhen Zhao

Publish Date: 2013/08/23

Volume: 33, Issue: 10, Pages: 727-736

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Abstract

The identification and quantification of potential drug–drug interactions is important for avoiding or minimizing the interactioninduced adverse events associated with specific drug combinations Clinical studies in healthy subjects were performed to evaluate potential pharmacokinetic interactions between vortioxetine Lu AA21004 and coadministered agents including fluconazole cytochrome P450 CYP 2C9 CYP2C19 and CYP3A inhibitor ketoconazole CYP3A and Pglycoprotein inhibitor rifampicin CYP inducer bupropion CYP2D6 inhibitor and CYP2B6 substrate ethinyl estradiol/levonorgestrel CYP3A substrates and omeprazole CYP2C19 substrate and inhibitorThe ratio of central values of the test treatment to the reference treatment for relevant parameters eg area under the plasma concentration–time curve AUC and maximum plasma concentration C max was used to assess pharmacokinetic interactionsCoadministration of vortioxetine had no effect on the AUC or C max of ethinyl estradiol/levonorgestrel or 5′hydroxyomeprazole or the AUC of bupropion the 90  confidence intervals for these ratios of central values were within 80–125  Steadystate AUC and C max of vortioxetine increased when coadministered with bupropion 128 and 114  respectively fluconazole 46 and 15  respectively and ketoconazole 30 and 26  respectively and decreased by 72 and 51  respectively when vortioxetine was coadministered with rifampicin Concomitant therapy was generally well tolerated most adverse events were mild or moderate in intensityVortioxetine Lu AA21004 1224dimethylphenylsulfanylphenylpiperazinehydrobromide is an investigational chemical entity under development by H Lundbeck A/S and Takeda Global Research Development Center Inc for the treatment of major depressive disorder MDD The in vitro pharmacological profile of vortioxetine is different from that of conventional antidepressants Vortioxetine is a multimodal compound that is thought to work through a combination of two pharmacological modes of action serotonin 5HT reuptake inhibition and receptor activity It functions as a 5HT3 5HT7 and 5HT1D receptor antagonist 5HT1A receptor agonist 5HT1B receptor partial agonist and inhibitor of the 5HT transporter 1 Preclinical studies demonstrated that vortioxetine enhances levels of the neurotransmitters serotonin noradrenaline dopamine acetylcholine and histamine in specific areas of the rat brain ie the ventral hippocampus and medial prefrontal cortex 1 2 The recommended dosage for vortioxetine in the treatment of MDD is 5–20 mg/day In clinical studies the commonly reported adverse events were nausea dry mouth diarrhea headache dizziness somnolence and nasopharyngitis 3 4 5The cytochrome P450 CYP450 pathway is important for the oxidative metabolism of various drugs and therefore implicated in drug–drug interactions 6 7 Such interactions are a major cause of adverse events with pharmacotherapy 8 Therefore the identification and quantification of these interactions in vivo is important for avoiding or minimizing the interactioninduced adverse events associated with specific drug combinations Despite the theoretical potential for serious drug–drug interactions a recent metaanalysis by Schellander and colleagues 9 showed that the frequency of clinically relevant interactions eg serotonin syndrome cardiac toxicity with antidepressants is relatively lowVortioxetine undergoes extensive metabolism primarily via oxidation and subsequent glucuronic acid conjugation In vitro data suggest that several CYP isoenzymes are involved in the oxidative metabolism of vortioxetine including CYP2D6 CYP3A4/5 CYP2C9 CYP2C19 CYP2A6 CYP2C8 and CYP2B6 10 Vortioxetine is metabolized to its major carboxylic acid metabolite Lu AA34443 pharmacologically inactive mainly via the CYP2D6 pathway A minor metabolite Lu AA39835 hydroxyl metabolite plasma metabolic ratio ≤4  showed similar 5HT transporter inhibition to the parent compound however based on a nonclinical pharmacology study this metabolite is not expected to penetrate the blood–brain barrier unpublished results

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