Back to Search
Start Over
Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers.
- Source :
-
Journal of cardiovascular electrophysiology [J Cardiovasc Electrophysiol] 2016 Oct; Vol. 27 (10), pp. 1206-1213. Date of Electronic Publication: 2016 Jul 25. - Publication Year :
- 2016
-
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.<br />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.<br />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.<br />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).<br />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.<br /> (© 2016 Wiley Periodicals, Inc.)
- Subjects :
- Action Potentials
Adolescent
Adult
Alkynes
Benzoxazines blood
Cyclopropanes
Cytochrome P-450 CYP2B6 metabolism
Dose-Response Relationship, Drug
ERG1 Potassium Channel metabolism
Electrocardiography
Female
Gene Frequency
Genotype
HEK293 Cells
Healthy Volunteers
Heart Rate drug effects
Homozygote
Humans
Male
Pharmacogenetics
Phenotype
Potassium Channel Blockers blood
Reverse Transcriptase Inhibitors blood
Risk Assessment
Risk Factors
Time Factors
Torsades de Pointes genetics
Torsades de Pointes metabolism
Torsades de Pointes physiopathology
Transfection
Young Adult
Benzoxazines adverse effects
Cytochrome P-450 CYP2B6 genetics
ERG1 Potassium Channel antagonists & inhibitors
Pharmacogenomic Variants
Potassium Channel Blockers adverse effects
Reverse Transcriptase Inhibitors adverse effects
Torsades de Pointes chemically induced
Subjects
Details
- Language :
- English
- ISSN :
- 1540-8167
- Volume :
- 27
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of cardiovascular electrophysiology
- Publication Type :
- Academic Journal
- Accession number :
- 27333947
- Full Text :
- https://doi.org/10.1111/jce.13032