Aline Hajj1, Kamilia Ksouda2, Katell Peoc'h3, Emmanuel Curis4, Anne Messali5, Laurence Labat Deveaux6, Vanessa Bloch7, Nathalie Prince7, Stéphane Mouly7, Jean-Michel Scherrmann7, Jean-Pierre Lépine2, Jean-Louis Laplanche3, Milou-Daniel Drici8, Florence Vorspan9. 1. INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France; AP-HP, Hôpital Lariboisière, Service de Biochimie et Biologie moléculaire, 2 rue Ambroise Paré, 75010 Paris, France; Pharmacology Unit, Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, Saint Joseph University, Beirut, Lebanon. 2. INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France; AP-HP, Hôpital Fernand Widal, Service de Psychiatrie, 200 rue du Fg St Denis, 75010 Paris, France. 3. INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France; AP-HP, Hôpital Lariboisière, Service de Biochimie et Biologie moléculaire, 2 rue Ambroise Paré, 75010 Paris, France. 4. INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France; Université Paris Descartes, Faculté de Pharmacie, Département de Biostatistiques, 4 avenue de l'Observatoire, 75006 Paris, France. 5. AP-HP, Hôpital Lariboisière, Service de Cardiologie, 2 rue Ambroise Paré, 75010 Paris, France. 6. AP-HP, Hôtel Dieu Service de Pharmacie - Pharmacologie - Toxicologie, 1 place du Parvis Notre Dame, 75004 Paris, France. 7. INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France. 8. Service de Pharmacologie, Hôpital Pasteur, 06000 Nice, France. 9. INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France; AP-HP, Hôpital Fernand Widal, Service de Psychiatrie, 200 rue du Fg St Denis, 75010 Paris, France. Electronic address: florence.vorspan@lrb.aphp.fr.
Abstract
BACKGROUND: Many drugs increase the duration of the QT interval of patients, potentially leading to harmful effects such as polymorphic ventricular arrhythmias. Most of these drugs do so by inhibiting the rapid component IKr of the delayed rectifier potassium current IK. Methadone is the most prescribed heroin maintenance treatment and is known to inhibit the cardiac potassium channel hERG, which recapitulates IKr. In order to evaluate if any polymorphism of potassium channels' genes could explain some of the "idiosyncratic" QT prolongations observed in patients treated with methadone, we tested the association between KCNE1, KCNE2, and KCNH2 polymorphism and the QT interval prolongation in those patients, controlling for other variables associated with a decrease of the repolarizing reserve. METHODS: A cohort of 82 patients treated with stable dosage of methadone (mean dosage 65 mg/d) for at least three months was genotyped for five polymorphisms in KCNE1, KCNE2 and KCNH2 genes and had their corrected QT (QTc) assessed. RESULTS: The mean QTc interval was 415±34ms. In a linear regression model, longer QTc interval was associated with methadone dosage and with one genetic factor. Each copy of a Lys allele at codon 897 of KCNH2, the gene that encodes the cardiac potassium voltage-gated channel hERG, was associated with a 15.4ms longer QTc (95% CI [4.6-26.2]; p=0.001). CONCLUSION: KCNH2 genotyping may be relevant in the analysis of cumulative risk factors for QT prolongation in patients on methadone maintenance treatment.
BACKGROUND: Many drugs increase the duration of the QT interval of patients, potentially leading to harmful effects such as polymorphic ventricular arrhythmias. Most of these drugs do so by inhibiting the rapid component IKr of the delayed rectifier potassium current IK. Methadone is the most prescribed heroin maintenance treatment and is known to inhibit the cardiac potassium channel hERG, which recapitulates IKr. In order to evaluate if any polymorphism of potassium channels' genes could explain some of the "idiosyncratic" QT prolongations observed in patients treated with methadone, we tested the association between KCNE1, KCNE2, and KCNH2 polymorphism and the QT interval prolongation in those patients, controlling for other variables associated with a decrease of the repolarizing reserve. METHODS: A cohort of 82 patients treated with stable dosage of methadone (mean dosage 65 mg/d) for at least three months was genotyped for five polymorphisms in KCNE1, KCNE2 and KCNH2 genes and had their corrected QT (QTc) assessed. RESULTS: The mean QTc interval was 415±34ms. In a linear regression model, longer QTc interval was associated with methadone dosage and with one genetic factor. Each copy of a Lys allele at codon 897 of KCNH2, the gene that encodes the cardiac potassium voltage-gated channel hERG, was associated with a 15.4ms longer QTc (95% CI [4.6-26.2]; p=0.001). CONCLUSION:KCNH2 genotyping may be relevant in the analysis of cumulative risk factors for QT prolongation in patients on methadone maintenance treatment.
Authors: Maartje N Niemeijer; Marten E van den Berg; Mark Eijgelsheim; Peter R Rijnbeek; Bruno H Stricker Journal: Drug Saf Date: 2015-10 Impact factor: 5.606