title: Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers.
abstract: Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele.
  
  
  
  The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening.
  
  
  
  EFV was administered to healthy volunteers (n = 57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression.
  
  
  
  EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ∆∆QTcF were observed at 6 hours (14 milliseconds; 95% CI [1; 27]), 12 hours (18 milliseconds; 95% CI [-4; 40]), and 18 hours (6 milliseconds; 95% CI [-1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 μg/mL significantly inhibited outward hERG tail currents (P < 0.05).
  
  
  
  This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG.
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Abdelhady
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette.
authors.forename: Tyler
authors.initials: T
authors.lastname: Shugg
authors.affiliation: Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Thong
authors.affiliation: Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Jessica Bo Li
authors.initials: JB
authors.lastname: Lu
authors.affiliation: Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kreutz
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Jaynes
authors.affiliation: Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Robarge
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette.|Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Tisdale
authors.affiliation: Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette. boverhol@purdue.edu.|Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, Indiana, USA. boverhol@purdue.edu.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Overholser
mesh_terms: D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D000480:Alkynes; D048588:Benzoxazines / Q000009:adverse effects* / Q000097:blood; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004562:Electrocardiography; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D057809:HEK293 Cells; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006720:Homozygote; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000009:adverse effects* / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000097:blood; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D014162:Transfection; D055815:Young Adult
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D018894:Reverse Transcriptase Inhibitors; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz
keywords: QTc; QTc interval prolongation; efavirenz; hERG; torsade de pointes