{"title":"维洛氮平缓释胶囊（Qelbree®）对某些细胞色素 P450 酶活性的影响以及评估 CYP2D6 基因多态性对维洛氮平药代动力学的影响","authors":"Zhao Wang, Tesfaye Liranso, Zulane Maldonado-Cruz, Alisa R. Kosheleff, Azmi Nasser","doi":"10.1007/s40261-024-01356-0","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and Objective</h3><p>Viloxazine extended-release (ER) [Qelbree<sup>®</sup>] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3–5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student’s <i>t</i> test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (<i>C</i><sub>max</sub>), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC<sub><i>t</i></sub>), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC<sub>∞</sub>) was 99.11 (95.84–102.49), 436.15 (398.87–476.92), and 583.35 (262.41–1296.80), respectively; 150.76 (126.03–180.35), 185.76 (155.01–222.61), and 189.71 (160.37–224.42) for dextromethorphan <i>C</i><sub>max</sub>, AUC<sub>t,</sub> and AUC<sub>∞</sub>, respectively; and 112.81 (104.71–121.54), 167.56 (153.05–183.45), and 168.91 (154.38–184.80) for midazolam <i>C</i><sub>max</sub>, AUC<sub><i>t</i>,</sub> and AUC<sub>∞</sub>, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were <i>C</i><sub>max</sub> 120.70 (102.33–142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC<sub>0–24</sub> 125.66 (105.36–149.87)).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":"38 1","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Impact of Viloxazine Extended-Release Capsules (Qelbree®) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics\",\"authors\":\"Zhao Wang, Tesfaye Liranso, Zulane Maldonado-Cruz, Alisa R. Kosheleff, Azmi Nasser\",\"doi\":\"10.1007/s40261-024-01356-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3 data-test=\\\"abstract-sub-heading\\\">Background and Objective</h3><p>Viloxazine extended-release (ER) [Qelbree<sup>®</sup>] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics.</p><h3 data-test=\\\"abstract-sub-heading\\\">Methods</h3><p>Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3–5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student’s <i>t</i> test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers.</p><h3 data-test=\\\"abstract-sub-heading\\\">Results</h3><p>The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (<i>C</i><sub>max</sub>), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC<sub><i>t</i></sub>), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC<sub>∞</sub>) was 99.11 (95.84–102.49), 436.15 (398.87–476.92), and 583.35 (262.41–1296.80), respectively; 150.76 (126.03–180.35), 185.76 (155.01–222.61), and 189.71 (160.37–224.42) for dextromethorphan <i>C</i><sub>max</sub>, AUC<sub>t,</sub> and AUC<sub>∞</sub>, respectively; and 112.81 (104.71–121.54), 167.56 (153.05–183.45), and 168.91 (154.38–184.80) for midazolam <i>C</i><sub>max</sub>, AUC<sub><i>t</i>,</sub> and AUC<sub>∞</sub>, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were <i>C</i><sub>max</sub> 120.70 (102.33–142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC<sub>0–24</sub> 125.66 (105.36–149.87)).</p><h3 data-test=\\\"abstract-sub-heading\\\">Conclusion</h3><p>Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.</p>\",\"PeriodicalId\":10402,\"journal\":{\"name\":\"Clinical Drug Investigation\",\"volume\":\"38 1\",\"pages\":\"\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2024-04-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Drug Investigation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40261-024-01356-0\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Drug Investigation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s40261-024-01356-0","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Impact of Viloxazine Extended-Release Capsules (Qelbree®) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics
Background and Objective
Viloxazine extended-release (ER) [Qelbree®] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics.
Methods
Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3–5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student’s t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers.
Results
The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUCt), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC∞) was 99.11 (95.84–102.49), 436.15 (398.87–476.92), and 583.35 (262.41–1296.80), respectively; 150.76 (126.03–180.35), 185.76 (155.01–222.61), and 189.71 (160.37–224.42) for dextromethorphan Cmax, AUCt, and AUC∞, respectively; and 112.81 (104.71–121.54), 167.56 (153.05–183.45), and 168.91 (154.38–184.80) for midazolam Cmax, AUCt, and AUC∞, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were Cmax 120.70 (102.33–142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC0–24 125.66 (105.36–149.87)).
Conclusion
Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.
期刊介绍：
Clinical Drug Investigation provides rapid publication of original research covering all phases of clinical drug development and therapeutic use of drugs. The Journal includes:
-Clinical trials, outcomes research, clinical pharmacoeconomic studies and pharmacoepidemiology studies with a strong link to optimum prescribing practice for a drug or group of drugs.
-Clinical pharmacodynamic and clinical pharmacokinetic studies with a strong link to clinical practice.
-Pharmacodynamic and pharmacokinetic studies in healthy volunteers in which significant implications for clinical prescribing are discussed.
-Studies focusing on the application of drug delivery technology in healthcare.
-Short communications and case study reports that meet the above criteria will also be considered.
Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in Clinical Drug Investigation may be accompanied by plain language summaries to assist readers who have some knowledge, but non in-depth expertise in, the area to understand important medical advances.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
