title: Evidence for the hERG Liability of Antihistamines, Antipsychotics, and Anti-Infective Agents: A Systematic Literature Review From the ARITMO Project.
abstract: A systematic review was performed to categorize the hERG (human ether-a-go-go-related gene) liability of antihistamines, antipsychotics, and anti-infectives and to compare it with current clinical risk of torsade de pointes (TdP). Eligible studies were hERG assays reporting half-minimal inhibitory concentrations (IC50). A "hERG safety margin" was calculated from the IC50 divided by the peak human plasma concentration (free Cmax). A margin below 30 defined hERG liability. Each drug was assigned an "uncertainty score" based on volume, consistency, precision, and internal and external validity of evidence. The hERG liability was compared to existing knowledge on TdP risk (www.credibledrugs.org). Of 1828 studies, 82 were eligible, allowing calculation of safety margins for 61 drugs. Thirty-one drugs (51%) had evidence of hERG liability including 6 with no previous mention of TdP risk (eg, desloratadine, lopinavir). Conversely, 16 drugs (26%) had no evidence of hERG liability including 6 with known, or at least conditional or possible, TdP risk (eg, chlorpromazine, sulpiride). The main sources of uncertainty were the validity of the experimental conditions used (antihistamines and antipsychotics) and nonuse of reference compounds (anti-infectives). In summary, hERG liability was categorized for 3 widely used drug classes, incorporating a qualitative assessment of the strength of available evidence. Some concordance with TdP risk was observed, although several drugs had hERG liability without evidence of clinical risk and vice versa. This may be due to gaps in clinical evidence, limitations of hERG/Cmaxdata, or other patient/drug-specific factors that contribute to real-life TdP risk.
authors.affiliation: Drug Safety Research Unit, Southampton, United Kingdom.
authors.forename: Lorna
authors.initials: L
authors.lastname: Hazell
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Raschi
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Ponti
authors.affiliation: Institute of Cellular Medicine, Faculty of Medicine, Newcastle University, Newcastle, United Kingdom.
authors.forename: Simon H L
authors.initials: SH
authors.lastname: Thomas
authors.affiliation: University of Bordeaux U657, CHU de Bordeaux, Bordeaux, France.
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvo
authors.affiliation: Drug Safety and Metabolism, AstraZeneca Innovative Medicines and Early Development, Mölndal, Sweden.
authors.forename: Ernst
authors.initials: E
authors.lastname: Ahlberg Helgee
authors.affiliation: Computational Toxicology, Swedish Toxicology Sciences Research Center, Södertälje, Sweden.
authors.forename: Scott
authors.initials: S
authors.lastname: Boyer
authors.affiliation: Medical Informatics, Erasmus University, Rotterdam, The Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Sturkenboom
authors.affiliation: Drug Safety Research Unit, Southampton, United Kingdom.
authors.forename: Saad
authors.initials: S
authors.lastname: Shakir
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006633:Histamine Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D012307:Risk Factors; D016171:Torsades de Pointes / Q000139:chemically induced*
chemical_list: D000890:Anti-Infective Agents; D014150:Antipsychotic Agents; D051638:Ether-A-Go-Go Potassium Channels; D006633:Histamine Antagonists
keywords: anti-infective agents; antipsychotic agents; ether-a-go-go potassium channels; histamine H1 antagonists; review