Yuan Zhao1, Mona Kotecha2, Helen Finnigan3, Michael Serenko2, Himanshu Naik4. 1. Quantitative Pharmacology, EMD Serono, 45 Middlesex Turnpike, Billerica, MA, 01821, USA. yzhao08@gmail.com. 2. Biogen, Cambridge, MA, USA. 3. Biogen, Maidenhead, UK. 4. Clinical Pharmacology, Sumitovant Biopharma, New York, NY, USA.
Abstract
BACKGROUND AND OBJECTIVE: Vixotrigine is a voltage-dependent and use-dependent sodium channel blocker in development for the treatment of neuropathic pain. Metabolism of vixotrigine is primarily through glucuronidation, resulting in the major M13 metabolite. Two additional major metabolites formed are M14 and M16. This study was designed to evaluate the effects of a uridine diphosphate-glucuronosyltransferase inhibitor, valproic acid, on vixotrigine pharmacokinetics. METHODS: This open-label, fixed-sequence, phase I study enrolled 30 healthy volunteers who received a single dose of vixotrigine 150 mg on day 1 and day 16 following an 8-h fast. On days 8-22, volunteers received valproic acid 500 mg three times daily. A mixed-effects model was used to analyze the effect of valproic acid on the natural log-transformed pharmacokinetic parameters of vixotrigine and its metabolites including maximum concentration and area under the concentration-time curve from time zero to infinity. RESULTS: Vixotrigine systemic exposure (area under the concentration-time curve from time zero to infinity) was increased by approximately 70% following the addition of valproic acid with a negligible effect on maximum concentration. Valproic acid administration also impacted vixotrigine metabolites: M13 exposure decreased by approximately 50% and M13 maximum concentration decreased by approximately 70%; increased exposure was noted for the M14 (approximately 100%) and M16 (approximately 70%) metabolites. CONCLUSIONS: Valproic acid, a uridine diphosphate-glucuronosyltransferase inhibitor, significantly increased vixotrigine systemic exposure. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03385525.
BACKGROUND AND OBJECTIVE: Vixotrigine is a voltage-dependent and use-dependent sodium channel blocker in development for the treatment of neuropathic pain. Metabolism of vixotrigine is primarily through glucuronidation, resulting in the major M13 metabolite. Two additional major metabolites formed are M14 and M16. This study was designed to evaluate the effects of a uridine diphosphate-glucuronosyltransferase inhibitor, valproic acid, on vixotrigine pharmacokinetics. METHODS: This open-label, fixed-sequence, phase I study enrolled 30 healthy volunteers who received a single dose of vixotrigine 150 mg on day 1 and day 16 following an 8-h fast. On days 8-22, volunteers received valproic acid 500 mg three times daily. A mixed-effects model was used to analyze the effect of valproic acid on the natural log-transformed pharmacokinetic parameters of vixotrigine and its metabolites including maximum concentration and area under the concentration-time curve from time zero to infinity. RESULTS: Vixotrigine systemic exposure (area under the concentration-time curve from time zero to infinity) was increased by approximately 70% following the addition of valproic acid with a negligible effect on maximum concentration. Valproic acid administration also impacted vixotrigine metabolites: M13 exposure decreased by approximately 50% and M13 maximum concentration decreased by approximately 70%; increased exposure was noted for the M14 (approximately 100%) and M16 (approximately 70%) metabolites. CONCLUSIONS: Valproic acid, a uridine diphosphate-glucuronosyltransferase inhibitor, significantly increased vixotrigine systemic exposure. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03385525.
Authors: Joanna M Zakrzewska; Joanne Palmer; Valerie Morisset; Gerard Mp Giblin; Mark Obermann; Dominik A Ettlin; Giorgio Cruccu; Lars Bendtsen; Mark Estacion; Dominique Derjean; Stephen G Waxman; Gary Layton; Kevin Gunn; Simon Tate Journal: Lancet Neurol Date: 2017-02-17 Impact factor: 44.182
Authors: David L Bennett; Alex J Clark; Jianying Huang; Stephen G Waxman; Sulayman D Dib-Hajj Journal: Physiol Rev Date: 2019-04-01 Impact factor: 37.312
Authors: G D Anderson; M K Yau; B E Gidal; S J Harris; R H Levy; A A Lai; K B Wolf; W A Wargin; A T Dren Journal: Clin Pharmacol Ther Date: 1996-08 Impact factor: 6.875
Authors: Yogita Ghodke-Puranik; Caroline F Thorn; Jatinder K Lamba; J Steven Leeder; Wen Song; Angela K Birnbaum; Russ B Altman; Teri E Klein Journal: Pharmacogenet Genomics Date: 2013-04 Impact factor: 2.089
Authors: Joi Dunbar; Mark Versavel; Yuan Zhao; Simon Tate; Valerie Morisset; Gerard M P Giblin; Joanne Palmer; Beth Tidemann-Miller; Himanshu Naik Journal: Clin Pharmacol Drug Dev Date: 2019-10-24