Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers

J Cardiovasc Electrophysiol. 2016 Oct;27(10):1206-1213. doi: 10.1111/jce.13032. Epub 2016 Jul 25.

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT02164812.

Keywords: QTc; QTc interval prolongation; efavirenz; hERG; torsade de pointes.

Publication types

  • Clinical Trial

MeSH terms

  • Action Potentials
  • Adolescent
  • Adult
  • Alkynes
  • Benzoxazines / adverse effects*
  • Benzoxazines / blood
  • Cyclopropanes
  • Cytochrome P-450 CYP2B6 / genetics*
  • Cytochrome P-450 CYP2B6 / metabolism
  • Dose-Response Relationship, Drug
  • ERG1 Potassium Channel / antagonists & inhibitors*
  • ERG1 Potassium Channel / metabolism
  • Electrocardiography
  • Female
  • Gene Frequency
  • Genotype
  • HEK293 Cells
  • Healthy Volunteers
  • Heart Rate / drug effects
  • Homozygote
  • Humans
  • Male
  • Pharmacogenetics
  • Pharmacogenomic Variants*
  • Phenotype
  • Potassium Channel Blockers / adverse effects*
  • Potassium Channel Blockers / blood
  • Reverse Transcriptase Inhibitors / adverse effects*
  • Reverse Transcriptase Inhibitors / blood
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • Torsades de Pointes / chemically induced*
  • Torsades de Pointes / genetics
  • Torsades de Pointes / metabolism
  • Torsades de Pointes / physiopathology
  • Transfection
  • Young Adult

Substances

  • Alkynes
  • Benzoxazines
  • Cyclopropanes
  • ERG1 Potassium Channel
  • KCNH2 protein, human
  • Potassium Channel Blockers
  • Reverse Transcriptase Inhibitors
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • efavirenz

Associated data

  • ClinicalTrials.gov/NCT02164812