title: Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect - comprehensive overview of clinical trials.
abstract: BACKGROUND
  Proarrhythmia assessment is one of the major concerns for regulatory bodies and pharmaceutical industry. ICH guidelines recommending preclinical tests have been established in attempt to eliminate the risk of drug-induced arrhythmias. However, in the clinic, arrhythmia occurrence is determined not only by the inherent property of a drug to block ion currents and disturb electrophysiological activity of cardiac myocytes, but also by many other factors modifying individual risk of QT prolongation and subsequent proarrhythmia propensity. One of those is drug-drug interactions. Since polypharmacy is a common practice in clinical settings, it can be anticipated that there is a relatively high risk that the patient will receive at least two drugs mutually modifying their proarrhythmic potential and resulting either in triggering the occurrence or mitigating the clinical symptoms. The mechanism can be observed either directly at the pharmacodynamic level by competing for the molecular targets, or indirectly by modifying the physiological parameters, or at the pharmacokinetic level by alteration of the active concentration of the victim drug.
  
  
  METHODS
  This publication provides an overview of published clinical studies on pharmacokinetic and/or pharmacodynamic drug-drug interactions in humans and their electrophysiological consequences (QT interval modification). Databases of PubMed and Scopus were searched and combinations of the following keywords were used for Title, Abstract and Keywords fields: interaction, coadministration, combination, DDI and electrocardiographic, QTc interval, ECG. Only human studies were included. Over 4500 publications were retrieved and underwent preliminary assessment to identify papers accordant with the topic of this review. 76 papers reporting results for 96 drug combinations were found and analyzed.
  
  
  RESULTS
  The results show the tremendous variability of drug-drug interaction effects, which makes one aware of complexity of the problem, and suggests the need for assessment of an additional risk factors and careful ECG monitoring before administration of drugs with anticipated QT prolongation.
  
  
  CONCLUSIONS
  DDIs can play significant roles in drugs' cardiac safety, as evidenced by the provided examples. Assessment of the pharmacodynamic effects of the drug interactions is more challenging as compared to the pharmacokinetic due to the significant diversity in the endpoints which should be analyzed specifically for various clinical effects. Nevertheless, PD components of DDIs should be accounted for as PK changes alone do not allow to fully explain the electrophysiological effects in clinic situations.
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Street, 30-688, Krakow, Poland. b.wisniowska@uj.edu.pl.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wiśniowska
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Street, 30-688, Krakow, Poland.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Tylutki
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9 Street, 30-688, Kraków, Poland.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Wyszogrodzka
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Street, 30-688, Krakow, Poland. spolak@cm-uj.krakow.pl.|Simcyp Ltd. (part of Certara), Blades Enterprise Centre, S2 4SU, Sheffield, UK. spolak@cm-uj.krakow.pl.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Polak
mesh_terms: D002986:Clinical Trials as Topic; D004347:Drug Interactions; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D010599:Pharmacokinetics