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

Ahmed M. Abdelhady, Tyler Shugg, Nancy Thong, Jessica Bo Li Lu, Yvonne Kreutz, Heather A. Jaynes, Jason D. Robarge, James E. Tisdale, Zeruesenay Desta, Brian R. Overholser

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1206-1213
Number of pages8
JournalJournal of Cardiovascular Electrophysiology
Volume27
Issue number10
DOIs
StatePublished - Oct 1 2016

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efavirenz
Ether
Alleles
Genotype
Cytochrome P-450 CYP2B6
Torsades de Pointes

Keywords

  • efavirenz
  • hERG
  • QTc
  • QTc interval prolongation
  • torsade de pointes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers. / Abdelhady, Ahmed M.; Shugg, Tyler; Thong, Nancy; Lu, Jessica Bo Li; Kreutz, Yvonne; Jaynes, Heather A.; Robarge, Jason D.; Tisdale, James E.; Desta, Zeruesenay; Overholser, Brian R.

In: Journal of Cardiovascular Electrophysiology, Vol. 27, No. 10, 01.10.2016, p. 1206-1213.

Research output: Contribution to journalArticle

Abdelhady, AM, Shugg, T, Thong, N, Lu, JBL, Kreutz, Y, Jaynes, HA, Robarge, JD, Tisdale, JE, Desta, Z & Overholser, BR 2016, 'Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers', Journal of Cardiovascular Electrophysiology, vol. 27, no. 10, pp. 1206-1213. https://doi.org/10.1111/jce.13032
Abdelhady, Ahmed M. ; Shugg, Tyler ; Thong, Nancy ; Lu, Jessica Bo Li ; Kreutz, Yvonne ; Jaynes, Heather A. ; Robarge, Jason D. ; Tisdale, James E. ; Desta, Zeruesenay ; Overholser, Brian R. / Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers. In: Journal of Cardiovascular Electrophysiology. 2016 ; Vol. 27, No. 10. pp. 1206-1213.
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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.",
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AU - Shugg, Tyler

AU - Thong, Nancy

AU - Lu, Jessica Bo Li

AU - Kreutz, Yvonne

AU - Jaynes, Heather A.

AU - Robarge, Jason D.

AU - Tisdale, James E.

AU - Desta, Zeruesenay

AU - Overholser, Brian R.

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N2 - 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.

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