Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications
Abstract Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associate...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-08-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13311 |
| _version_ | 1811216609888436224 |
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| author | Lindsey Ingleby‐Talecki Sven C. vanDijkman Sean P. Oosterholt Oscar Della Pasqua Christina Winter Marianne Cunnington Linda Rebar Sergio Forero‐Schwanhaeuser Vickas Patel James A. Cooper Anthony Bahinski Khuram W. Chaudhary |
| author_facet | Lindsey Ingleby‐Talecki Sven C. vanDijkman Sean P. Oosterholt Oscar Della Pasqua Christina Winter Marianne Cunnington Linda Rebar Sergio Forero‐Schwanhaeuser Vickas Patel James A. Cooper Anthony Bahinski Khuram W. Chaudhary |
| author_sort | Lindsey Ingleby‐Talecki |
| collection | DOAJ |
| description | Abstract Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan‐Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors, including mexiletine, do not slow cardiac conduction as measured by the electrocardiogram, at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of NaV1.5 block and to support the observed clinical safety of lamotrigine. We used HEK‐293 cells stably expressing the hNaV1.5 channel and voltage clamp electrophysiology to quantify the potency (half‐maximal inhibitory concentration) against peak and late channel current, on‐/off‐rate binding kinetics, voltage‐dependence, and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine), and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late NaV1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak NaV1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder. |
| first_indexed | 2024-04-12T06:42:04Z |
| format | Article |
| id | doaj.art-ffc94c4b636d4871bfe7eb3ce9458faa |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-04-12T06:42:04Z |
| publishDate | 2022-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-ffc94c4b636d4871bfe7eb3ce9458faa2022-12-22T03:43:42ZengWileyClinical and Translational Science1752-80541752-80622022-08-011581978198910.1111/cts.13311Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implicationsLindsey Ingleby‐Talecki0Sven C. vanDijkman1Sean P. Oosterholt2Oscar Della Pasqua3Christina Winter4Marianne Cunnington5Linda Rebar6Sergio Forero‐Schwanhaeuser7Vickas Patel8James A. Cooper9Anthony Bahinski10Khuram W. Chaudhary11GSK Global Non‐Clinical Safety Collegeville Pennsylvania USAGSK Clinical Pharmacology Modelling and Simulation Brentford UKGSK Clinical Pharmacology Modelling and Simulation Brentford UKGSK Clinical Pharmacology Modelling and Simulation Brentford UKGSK Clinical Safety and Pharmacovigilance Brentford UKGSK Epidemiology, Value Evidence & Outcomes Stevenage UKGSK US Regulatory Affairs Collegeville Pennsylvania USAGSK, US Medical Affairs Philadelphia Pennsylvania USAFormer GSK Employee Collegeville Pennsylvania USAGSK General Medicines Brentford UKGSK Global Non‐Clinical Safety Collegeville Pennsylvania USAGSK Global Non‐Clinical Safety Collegeville Pennsylvania USAAbstract Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan‐Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors, including mexiletine, do not slow cardiac conduction as measured by the electrocardiogram, at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of NaV1.5 block and to support the observed clinical safety of lamotrigine. We used HEK‐293 cells stably expressing the hNaV1.5 channel and voltage clamp electrophysiology to quantify the potency (half‐maximal inhibitory concentration) against peak and late channel current, on‐/off‐rate binding kinetics, voltage‐dependence, and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine), and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late NaV1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak NaV1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder.https://doi.org/10.1111/cts.13311 |
| spellingShingle | Lindsey Ingleby‐Talecki Sven C. vanDijkman Sean P. Oosterholt Oscar Della Pasqua Christina Winter Marianne Cunnington Linda Rebar Sergio Forero‐Schwanhaeuser Vickas Patel James A. Cooper Anthony Bahinski Khuram W. Chaudhary Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications Clinical and Translational Science |
| title | Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications |
| title_full | Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications |
| title_fullStr | Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications |
| title_full_unstemmed | Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications |
| title_short | Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications |
| title_sort | cardiac sodium channel inhibition by lamotrigine in vitro characterization and clinical implications |
| url | https://doi.org/10.1111/cts.13311 |
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