Clin Pharmacokinet DOI 10.1007/s40262-016-0407-2 REVIEW ARTICLE Drug–Drug Interactions Between Direct-Acting Antivirals and Psychoactive Medications 1 2 3 4 E. J. Smolders • C. T. M. M. de Kanter • R. J. de Knegt • M. van der Valk • 5 1 J. P. H. Drenth • D. M. Burger Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Treatment options for chronic hepatitis C virus psychoactive drugs and identify safe options for the (HCV) infection have drastically changed since the simultaneous treatment of mental illnesses and chronic development and licensing of new potent direct-acting HCV infection. antivirals (DAAs). The majority of DAAs are extensively metabolized by liver enzymes and have the ability to influence cytochrome P450 (CYP) enzymes. Additionally, Key Points these DAAs are both substrates and inhibitors of drug transporters, which makes the DAAs both possible victims Escitalopram and citalopram have been studied in or perpetrators of drug–drug interactions (DDIs). There is a combination with most direct-acting antivirals high prevalence of mental illnesses such as depression or (DAAs) and either of these drugs can be safely psychosis in HCV-infected patients; therefore, psychoac- combined with hepatitis C virus (HCV) treatment. tive medications are frequently co-administered with DAAs. The majority of these psychoactive medications are No formal interaction studies between psychoactive also metabolized by CYP enzymes but remarkably little agents and sofosbuvir or ledipasvir have been information is available on DDIs between psychoactive performed in humans. However, these DAAs are medications and DAAs. Hence, the aim of this review is to generally neither victims nor perpetrators of drug provide an overview of the interaction mechanisms interactions and can therefore be safely used in between DAAs and psychoactive agents. In addition, we combination with psychoactive drugs. describe evidenced-based interactions between DAAs and Boceprevir, simeprevir, and the combination paritaprevir/ritonavir plus ombitasvir with dasabuvir are most likely to cause drug interactions via the & D. M. Burger inhibition of cytochrome P450 (CYP) 3A4. [email protected] Therefore, caution must be exercised when CYP3A4 1 Department of Pharmacy, Radboud university medical center, substrates such as midazolam and/or quetiapine are Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The co-administered with these DAAs. Netherlands 2 Department of Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands 3 Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands 1 Introduction 4 Division of Infectious Diseases, Academic Medical Center, Center for Infection and Immunity Amsterdam (CINIMA), Amsterdam, The Netherlands One of the components previously used in the treatment 5 Department of Gastroenterology and Hepatology, Radboud regimen for hepatitis C virus (HCV) is pegylated inter- university medical center, Nijmegen, The Netherlands feron; however, it has major adverse effects on mental E. J. Smolders et al. health and depression was a commonly seen adverse event Little information is available on interactions between [1]. Since the development of novel direct-acting antivirals DAAs and psychoactive agents. Therefore, the aim of this (DAAs), pegylated interferon is no longer used in the review is to provide an overview of the interaction mech- treatment of HCV infections in resource-rich settings. anisms of DAAs and psychoactive agents. In addition, we However, the prevalence of mental disorders remains high describe evidenced-based interactions between DAAs and among untreated HCV-infected patients [2]. For example, a psychoactive drugs and identify safe options for treatment retrospective study reported that 86 % of HCV-infected of the simultaneous treatment of mental illnesses and HCV patients had at least one psychiatric, drug-, or alcohol use- infection. related disorder recorded in their patient charts. The most common conditions were depressive disorders (50 %), psychosis (50 %), anxiety disorders (41 %), post-traumatic 2 Methods stress disorders (34 %), and bipolar disorders (16 %) [3]. Another study reported a prevalence of 41 % for anxiety We searched PubMed (1946–January 2016) and EMBASE and 27 % for depression in HCV-infected individuals (1947–January 2016) to identify peer-reviewed studies. (n = 395) [4]. One explanation for this high prevalence The search covered all DAAs recommended in European was that patients with mental disorders are more likely to and US guidelines [11, 12] and licensed by the European have a drug addiction, because intravenous drug use is a Medicines Agency (EMA) and US Food and Drug major route of HCV transmission [5]. Administration (FDA). The DAAs included protease inhi- The results from a cross-sectional study were in agree- bitors (PIs) (boceprevir, simeprevir, paritaprevir, and gra- ment with the high prevalence of mental disorders. In that zoprevir), NS5A inhibitors (daclatasvir, ledipasvir, study, 16 % of the HCV-infected patients were on antide- ombitasvir, and elbasvir), and NS5B polymerase inhibitors pressants and 10 % were on antipsychotics (n = 3716) [6]. (sofosbuvir and dasabuvir). Telaprevir (PI) was excluded This corresponds with data from a Dutch nationwide sur- from the review because it has limited use in current vey in which benzodiazepines, drugs used for treating therapy. We also referred to the work published by Kiser opioid dependence, and selective serotonin reuptake inhi- and colleagues [13] for more information about telaprevir bitors (SSRIs) were among the drugs most frequently used and DDIs between DAAs and psychoactive drugs. by chronic HCV-infected patients [7]. The psychoactive agents included were SSRIs, TCAs, The use of antipsychotics and antidepressants during typical and atypical antipsychotics, benzodiazepines, DAA therapy increases the risk of drug-drug interactions monoamine oxidase inhibitors, lithium, and St John’s wort. (DDIs). Both DAAs and psychoactive agents are exten- The Google and Google Scholar search engines, and sively metabolized in the liver and have the ability to affect ClinicalTrials.gov (http://www.clinicaltrials.gov) website the activities of various enzymes (e.g., cytochrome P450 and the Liverpool drug interaction database (http://www. [CYP]) and drug transporters (e.g., P-glycoprotein [P-gp]). hep-druginteractions.org) were used to identify conference This makes DAAs as well as psychoactive agents possible papers and abstracts. All searches were performed in victims (objects of DDIs) and perpetrators (causes of DDIs) English. The search items contained generic and/or brand of drug interactions, which could negatively affect treat- names of the drugs and included terms such as antide- ment outcomes as a result of adverse effects (increased pressant, antipsychotic, sedative, and tranquilizer. plasma concentrations) or treatment failure (decreased Information about the pharmacokinetics and metabolism plasma concentrations) [8, 9]. In order to interpret the DDIs of the DAAs and psychoactive agents were obtained from between DAAs and psychoactive agents, it is important to the Summary of Product Characteristics (SmPC) and FDA have sufficient knowledge of their therapeutic ranges. prescribing information for each drug as well as from the Benzodiazepines, tricyclic antidepressants (TCAs), and Lexicomp database (available via http://www.uptodate. antipsychotics have a narrow therapeutic range, while com). Enzyme inhibitors and inducers were defined as SSRIs have a broad therapeutic range. Generally, drugs being strong, moderate, or weak if they changed the area with narrow therapeutic ranges are more likely to have under the plasma concentration–time curve (AUC) of a clinically relevant DDIs than drugs with large therapeutic substrate by 5-fold, [2to\5-fold, and \2-fold, respec- ranges [10]. DAAs have a large therapeutic range, which tively. Substrates were also grouped as being minor and makes them less susceptible to the effects of an increase or major substrates of enzymes. These groupings were based decrease in their plasma concentrations caused by, for on the clinical relevance of the potential interaction example, CYP inhibition or induction. However, extremely described by Lexicomp (http://www.uptodate.com) low plasma concentrations could lead to virologic failure. [14, 15]. DDIs Between DAAs and Psychoactive Medications 3 Drug-Drug Interaction (DDI) Mechanisms: 42 %, respectively. As a result of this, a reduction in the Direct-Acting Antivirals (DAAs) dose of furosemide of up to 50 % might be required if the drugs have to be co-administered [20]. In this section, we elaborate on the mechanisms by which DAAs can be perpetrators and/or victims of DDIs. We 3.2 Phase I and II Reactions: DAAs as Victims focused on interactions through hepatic drug metabolism and drug transporters because they are the most important DAAs, e.g., daclatasvir, simeprevir, grazoprevir, and pathways underlying interactions between DAAs and elbasvir, are predominantly metabolized by CYP3A4/5 in psychoactive agents. These mechanisms are illustrated the liver and gastrointestinal tract. Thus, caution is needed using examples of drug interactions between DAAs and when DAAs are administered with strong inducers or psychoactive agents or non-psychoactive drugs, which inhibitors of CYP3A4. A reduced plasma concentration of were studied in healthy volunteers. DAAs creates a potential