{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,5]],"date-time":"2025-07-05T08:24:18Z","timestamp":1751703858605},"reference-count":9,"publisher":"Georg Thieme Verlag KG","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Drug Res (Stuttg)"],"published-print":{"date-parts":[[2020,10]]},"abstract":"Abstract<\/jats:title>\n Aim This study assessed the linearity of pharmacokinetics (PK) of\n trimetazidine (TMZ) modified-release tablets (indicated in adults as an add-on\n therapy for stable angina pectoris) and measured its renal elimination, safety,\n and tolerability in healthy subjects.<\/jats:p>\n Methods This was a randomized, open-label, single-ascending dose study in\n healthy subjects. Subjects were administered with a single dose of 35, 70, or\n 105\u2009mg TMZ-modified release tablets (six subjects each). Pharmacokinetic\n evaluations and safety analysis were performed before the first dose and till\n 48\u2009h post-first dose.<\/jats:p>\n Results Following administration of 35, 70, and 105\u2009mg\n TMZ-modified release; the Cmax (mean\u00b1SD) was 79.32\n (\u00b123.08), 153.17 (\u00b123.08), and 199.67 (\u00b123.08)\n ng\/mL, the Tmax was 5.42 (\u00b10.49), 4.51\n (\u00b11.27), and 4.57 (\u00b10.96) h, t1\/2 was 7.75\n (\u00b11.62), 6.40 (\u00b11.23), and 6.50 (\u00b11.18) h,\n AUC(0-inf) was 1116.89 (\u00b1378.35), 1838.39\n (\u00b1284.50), and 2504.84 (\u00b1348.35) ng.h\/mL, CLR\n was 13.70 (\u00b12.24), 14.80 (\u00b15.91), and 19.58 (\u00b16.24)\n L\u00b7h\u22121 and CL\/F was 33.69 (\u00b18.51),\n 38.85 (\u00b16.15), and 42.74 (\u00b17.10)\n L\u00b7h\u22121, respectively. Slope estimates for\n AUC(0-inf), AUC(0-t), and Cmax were less\n than 1. Corresponding 95% CI of the slope for the AUC parameters\n excluded 1, indicating that the deviation from dose-proportionality was\n statistically significant. Corresponding 95% CI of the slope for\n Cmax included 1, indicating that the less than dose-proportional\n increase in Cmax was not statistically significant. No significant\n adverse events were observed.<\/jats:p>\n Conclusion Substantial deviation from a dose-proportional increase in\n AUC(0-inf) and AUC(0-t) suggested a non-linear PK for\n TMZ-modified release. Single dose of TMZ-modified release was well tolerated and\n safe.<\/jats:p>","DOI":"10.1055\/a-1180-4357","type":"journal-article","created":{"date-parts":[[2020,9,4]],"date-time":"2020-09-04T22:45:13Z","timestamp":1599259513000},"page":"472-477","source":"Crossref","is-referenced-by-count":4,"title":["Single Ascending Dose Study to Assess Pharmacokinetic Linearity,\n Safety, and Tolerability of Trimetazidine - Modified Release in Healthy Human\n Subjects"],"prefix":"10.1055","volume":"70","author":[{"given":"Thomas","family":"K\u00f6rnicke","sequence":"additional","affiliation":[{"name":"Parexel International GmbH, Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepa","family":"Arora","sequence":"additional","affiliation":[{"name":"Drug Safety and Risk Management, Lupin Limited (India), Mumbai,\n India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdus","family":"Samad","sequence":"additional","affiliation":[{"name":"Drug Safety and Risk Management, Lupin Limited (India), Mumbai,\n India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sigal","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Teva Pharmaceutical Industries LTD, Petach Tikva, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00f3nika","family":"Domahidy","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, Gedeon Richter Plc. Budapest,\n Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanka","family":"de Voogd","sequence":"additional","affiliation":[{"name":"Clinical Development Mylan EPD, Amstelveen, the\n Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stella","family":"B\u00f6hmert","sequence":"additional","affiliation":[{"name":"Sandoz International GmbH, Holzkirchen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita Silveira","family":"Ramos","sequence":"additional","affiliation":[{"name":"Generis\u00ae Farmac\u00eautica, Amadora, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shashank","family":"Jain","sequence":"additional","affiliation":[{"name":"Drug Safety and Risk Management, Lupin Limited (India), Mumbai,\n India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2020,9,4]]},"reference":[{"key":"ref2","doi-asserted-by":"publisher","first-page":"221","DOI":"10.3109\/00498259609046702","article-title":"Identification of trimetazidine metabolites in human urine and plasma","volume":"26","author":"P J Jackson","year":"1996","journal-title":"Xenobiotica"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1002\/bdd.350","article-title":"Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ\n MR 35 mg) in the elderly and patients with renal failure","volume":"24","author":"J Barr\u00e9","year":"2003","journal-title":"Biopharm Drug Dispos"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"331","DOI":"10.2165\/00129784-200505050-00006","article-title":"Modified-release formulation of trimetazidine for exceptional control of angina\n pectoris: Fact or fiction","volume":"5","author":"U Thadani","year":"2005","journal-title":"Am J Cardiovasc Drugs"},{"key":"ref6","first-page":"21654.","article-title":"Effect of age and renal impairment on the pharmacokinetics and safety of\n trimetazidine: An open-label multiple-dose study","author":"N Nenchev","year":"2020","journal-title":"Drug Dev Res"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"461","DOI":"10.7326\/0003-4819-130-6-199903160-00002","article-title":"A more accurate method to estimate glomerular filtration rate from serum\n creatinine: A new prediction equation","volume":"130","author":"A S Levey","year":"1999","journal-title":"Ann Intern Med"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1177\/0091270011422813","article-title":"Food effect on bioavailability of modified-release trimetazidine tablets","volume":"52","author":"L Ozbay","year":"2012","journal-title":"J Clin Pharmacol"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"e871","DOI":"10.1097\/MJT.0000000000000180","article-title":"Trimetazidine in Practice","volume":"23","author":"C A D\u00e9zsi","year":"2016","journal-title":"Am J Ther"},{"key":"ref10","first-page":"11","article-title":"The (PRIMA) Study. Comparison of clinical effect of trimetazidine MR in men and\n women","volume":"51","author":"I A Vasiuk","year":"2011","journal-title":"Kardiologiia"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"329","DOI":"10.2165\/00003088-200241050-00002","article-title":"How Important Are Gender Differences in Pharmacokinetics?","volume":"41","author":"B Meibohm","year":"2002","journal-title":"Clin Pharmacokinet"}],"container-title":["Drug Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-1180-4357.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T22:38:03Z","timestamp":1601332683000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-1180-4357"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,4]]},"references-count":9,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,9,28]]},"published-print":{"date-parts":[[2020,10]]}},"URL":"https:\/\/doi.org\/10.1055\/a-1180-4357","relation":{},"ISSN":["2194-9379","2194-9387"],"issn-type":[{"value":"2194-9379","type":"print"},{"value":"2194-9387","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,4]]}}}