title: Clinical pharmacology of multiple doses of lasofoxifene in postmenopausal women.
abstract: Lasofoxifene, a next-generation selective estrogen receptor modulator, is undergoing phase 3 clinical development for osteoporosis. This study evaluated daily lasofoxifene for 14 days in healthy postmenopausal women. A loading dose of 5 times the daily dose was followed by daily doses of 0.01 mg (n = 8), 0.03 mg (n =8), 0.1 mg(n = 16), 0.3 mg (n =9), 1 mg (n = 8), or placebo (n = 16). Samples were collected for pharmacokinetic and pharmacodynamic assessments. Lasofoxifene was well tolerated; study drug-associated adverse events were mild and unrelated to dose. There was a predictable increase in plasma concentrations of lasofoxifene with dose. Pharmacokinetic parameters included mean half-life of 165 hours, mean area under the plasma concentration-time curve from time 0 to 24 hours ranging from 1.67 ng x h/mL to 137 ng x h/mL, and mean maximum observed plasma concentration ranging from 0.09 ng/mL to 6.43 ng/mL. Lasofoxifene partially suppressed luteinizing hormone, follicle-stimulating hormone, low-density lipoprotein, and N-telopeptide.
authors.affiliation: Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Gardner
authors.forename: Ann
authors.initials: A
authors.lastname: Taylor
authors.forename: Greg
authors.initials: G
authors.lastname: Wei
authors.forename: Albert
authors.initials: A
authors.lastname: Calcagni
authors.forename: Barbara
authors.initials: B
authors.lastname: Duncan
authors.forename: Ashley
authors.initials: A
authors.lastname: Milton
mesh_terms: D000284:Administration, Oral; D008078:Cholesterol, LDL / Q000097:blood; D024042:Collagen Type I / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008875:Middle Aged; D010455:Peptides / Q000097:blood; D017698:Postmenopause / Q000378:metabolism*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D008078:Cholesterol, LDL; D024042:Collagen Type I; D010455:Peptides; D011759:Pyrrolidines; D020845:Selective Estrogen Receptor Modulators; D013764:Tetrahydronaphthalenes; C052929:collagen type I trimeric cross-linked peptide; C111332:Lasofoxifene; D007986:Luteinizing Hormone