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.

Effects of three cytochrome P450 inhibitors, ketoconazole, fluconazole, and paroxetine, on the pharmacokinetics of lasofoxifene

“…As stated in the FDA Guidance for Industry on Drug Metabolism [21], it is necessary to determine the metabolic pathways and routes of elimination of new drugs to ensure their safety and to understand the potential for drug-drug interactions. Lasofoxifene elimination is slow, with a t 1/2 of 5-6 days [6]. Renal excretion of unchanged lasofoxifene accounts for only 2% of the dose, whereas metabolism, including oxidation and conjugation pathways, appears to play a more important role.…”

“…In this study, lasofoxifene was shown not to have detrimental effects on the endometrium, which is a significant advantage over oestrogen [5]. Multiple doses ranging from 0.01 to 1 mg daily were administered in postmenopausal women [6]. Lasofoxifene pharmacokinetics were linear and the treatments were well tolerated [6].…”

“…Following each collection, blood samples were centrifuged as soon as possible and the separated plasma was stored frozen at ≤− 20 ° C until assayed. Plasma concentrations of lasofoxifene were measured using a validated liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method at CEDRA Corporation (Austin, TX, USA) [6]. The analytical range was 0.025-6 ng ml − 1 , with a lower limit of quantification of 0.025 ng ml − 1 .…”

“…Multiple doses ranging from 0.01 to 1 mg daily were administered in postmenopausal women [6]. Lasofoxifene pharmacokinetics were linear and the treatments were well tolerated [6]. The effects on bone have been studied in Phase 2 clinical trials in humans [7][8][9][10] and lasofoxifene is currently undergoing evaluation in Phase 3 clinical trials.…”

“…It has a long t 1/2 in humans (6-7 days) [6], which may be partly due to enterohepatic recirculation of its glucuronide/sulphate conjugates. Five main pathways of lasofoxifene metabolism have been identified in humans, involving both oxidation and conjugation ( Figure 1).…”