Evaluation of the effect of lasofoxifene (LASO) on the pharmacokinetics (PK) of digoxin

Abstract

Background LASO, a next-generation selective estrogen receptor modulator, is in late stage development for the prevention and treatment of osteoporosis. LASO has a long half-life (6 days) and less than 2% of the dose is recovered unchanged in urine. Both oxidative and conjugative metabolism contribute to its elimination. Digoxin is commonly prescribed for arrhythmias and congestive heart failure, has a narrow therapeutic index and may be coadministered with LASO. Objectives To determine the effect of LASO on the steady-state PK of digoxin. Methods This was a 2-period, fixed-sequence study in 12 healthy postmenopausal women. During days 1–20, all subjects received digoxin (0.25 mg/day). On day 11, all subjects received 4 mg loading dose of LASO followed by 0.5 mg/day on days 12–20. On Days 10 and 20, blood and urine samples were collected for up to 24 hours for determination of digoxin concentrations. The 90% CI of least squares mean ratio for Cmax and AUC was calculated. Results LASO had no effect on digoxin plasma PK with ratio (90% CI) of 95.4% (84.6% to 107%) and 103% (97.7% to 108%) for Cmax and AUC0-24, respectively. Results were within the 80% to 125% acceptance range. However, the ratio of Ae% was 127% (116% to 142%). Conclusions Coadministration of LASO had no effect on the steady-state pharmacokinetics of digoxin. Clinical Pharmacology & Therapeutics (2005) 77, P45–P45; doi: 10.1016/j.clpt.2004.12.064