{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T04:04:26Z","timestamp":1758945866537},"reference-count":23,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2008,9,22]],"date-time":"2008-09-22T00:00:00Z","timestamp":1222041600000},"content-version":"vor","delay-in-days":2397,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2002,3]]},"abstract":"<jats:p><jats:bold>Aims\u2002<\/jats:bold> The safety, pharmacodynamics and pharmacokinetics of levormeloxifene, a selective oestrogen receptor modulator (SERM), were investigated in postmenopausal women following single doses and multiple dosing once daily up to 56 days.<\/jats:p><jats:p><jats:bold>Methods\u2002<\/jats:bold> The two randomized, double\u2010blind, placebo controlled studies of six single ascending doses and at four multiple dose levels, respectively, included a total of 104 healthy postmenopausal women. Safety assessments comprised vital signs, ECG, haematology, clinical chemistry and reporting of adverse events. The pharmacodynamic properties were investigated after multiple dosing by assessment of the short\u2010term effects on bone and lipid metabolism and on the hypothalamic\u2010pituitary axis. Blood samples for pharmacokinetic analysis were collected at intervals until 648\u2003h (27 days) after single and multiple dosing.<\/jats:p><jats:p><jats:bold>Results<\/jats:bold> Levormeloxifene was tolerated well after single doses in the range of 2.5\u2013320\u2003mg and multiple once daily dosing in the range of 20\u2013160\u2003mg. Adverse events reported were generally mild or moderate. The most frequent adverse events after multiple dosing were headache, abdominal pain and leukorrhea with the highest frequency reported after the highest daily dose of 160\u2003mg levormeloxifene. Five weeks of treatment with 20\u2013160\u2003mg levormeloxifene and 8 weeks of treatment with 40 or 80\u2003mg levormeloxifene reduced the biochemical marker of bone turnover, the collagen I C\u2010terminal telopeptide (CrossLaps<jats:sup>TM<\/jats:sup>) by 44.4% [95% CI: 11.3, 65.1] and 35.5% [95% CI: 14.0, 51.6], respectively, without any dose\u2010dependent decrease in the studied dose range. The total cholesterol and LDL\u2010cholesterol concentrations were significantly reduced by 19\u201325% and 28\u201335%, respectively, when compared with placebo. HDL\u2010cholesterol and triglyceride concentrations were not affected. An oestrogen\u2010like effect on the hypothalamic\u2010pituitary axis was observed with approximately 50% reductions of FSH and LH after 8 weeks of treatment. No clinically significant changes of other safety variables were observed. The pharmacokinetic analysis demonstrated a rapid absorption (mean <jats:italic>t<\/jats:italic><jats:sub>max<\/jats:sub>: 2\u20133\u2003h), a slow elimination (mean <jats:italic>t<\/jats:italic><jats:sub>\u00bd<\/jats:sub>: 4.8\u20138.4 days) and dose linearity of <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> and AUC for doses up to 160\u2003mg. As expected for a drug with slow elimination given frequently, the relative fluctuation around the steady state plasma concentration was small and the drug accumulation considerable (R<jats:sub>A<\/jats:sub>: 3\u20135).<\/jats:p><jats:p><jats:bold>Conclusions<\/jats:bold> Short\u2010term administration of levormeloxifene in postmenopausal women was well\u2010tolerated at doses that elicited a favourable pharmacodynamic response suggesting oestrogen\u2010like bone preserving and antiatherogenic effects. Little variation of peak\u2010trough plasma concentrations was observed during daily administration due to a plasma half\u2010life of approximately 1 week.<\/jats:p>","DOI":"10.1046\/j.0306-5251.2001.01181.x","type":"journal-article","created":{"date-parts":[[2003,3,11]],"date-time":"2003-03-11T04:44:46Z","timestamp":1047357886000},"page":"284-295","source":"Crossref","is-referenced-by-count":15,"title":["Levormeloxifene: safety, pharmacodynamics and pharmacokinetics in healthy postmenopausal women following single and multiple doses of a new selective oestrogen receptor modulator"],"prefix":"10.1111","volume":"53","author":[{"given":"Birte K.","family":"Skrumsager","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedicte","family":"Kiehr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Poul Christian","family":"Pedersen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mireille","family":"Gerrits","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norma","family":"Watson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ketil","family":"Bjarnason","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2008,9,22]]},"reference":[{"key":"e_1_2_5_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910430506"},{"key":"e_1_2_5_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02738967"},{"key":"e_1_2_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(95)90247-3"},{"key":"e_1_2_5_5_2","doi-asserted-by":"publisher","DOI":"10.1177\/106002809703100615"},{"key":"e_1_2_5_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.313.7066.1205d"},{"key":"e_1_2_5_7_2","first-page":"1500","article-title":"Hormone replacement therapy\u2014risks and benefits","volume":"87","author":"Davey DA","year":"1997","journal-title":"S Afr Med J"},{"issue":"1","key":"e_1_2_5_8_2","first-page":"F484","article-title":"Levormeloxifene, a non\u2010steroidal, partial estrogen agonist, prevents bone loss, reduces serum\u2010cholesterol and exerts a non\u2010proliferative action on uterine tissues in the ovariectomized rat","volume":"12","author":"Bain S","year":"1997","journal-title":"J Bone Miner Res"},{"issue":"1","key":"e_1_2_5_9_2","first-page":"144","article-title":"Levormeloxifene, a non\u2010steroidal estrogen receptor therapeutic, prevents bone loss, reduces serum cholesterol and has differentiated uterine effects in the ovariectomized rat","volume":"27","author":"Bain S","year":"1997","journal-title":"Maturitas"},{"key":"e_1_2_5_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.17.10.2264"},{"key":"e_1_2_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0378-5122(97)81287-x"},{"issue":"1","key":"e_1_2_5_12_2","first-page":"F483","article-title":"Effect of levormeloxifene, a partial estrogen\u2010receptor agonist, on serum\u2010cholesterol, osteocalcin and bone in the ovariectomized rat","volume":"12","author":"Nowak J","year":"1997","journal-title":"J Bone Miner Res"},{"key":"e_1_2_5_13_2","unstructured":"World Medical Association's Declaration of Helsinki. 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