Disposition of lasofoxifene, a next-generation selective estrogen receptor modulator, in healthy male subjects.

Disposition of lasofoxifene, a next-generation selective estrogen receptor modulator, was investigated in male volunteers after p.o. administration of a single 20-mg dose of [(14)C]lasofoxifene. Approximately 72% of the administered dose was recovered from the urine and feces, with majority of dose excreted in the feces, probably via bile. The absorption of lasofoxifene in humans was slow with T(max) values typically exceeding 6 h. The C(max) and area under plasma concentration-time profile from time 0 to the last quantifiable time point values of lasofoxifene were lower than those determined for total radioactivity, indicating presence of circulating metabolites. The primary clearance mechanisms for lasofoxifene in humans were direct conjugation (glucuronide and sulfate conjugates) and phase I oxidation, each accounting for about half of the metabolism. Several oxidative metabolites were identified by liquid chromatography/tandem mass spectrometry. The primary phase I metabolites were the result of hydroxylations on the tetraline moiety and the phenyl rings attached to the tetraline, and oxidation on the pyrrolidine moiety. Considering the numerous metabolites seen in vivo, additional in vitro studies using human liver and intestinal microsomes, recombinant cytochromes P450 (P450s), and UDP glucuronosyltransferases (UGTs) were performed. The turnover of lasofoxifene was very slow in liver microsomes, and only two metabolites were identified as two regioisomers of the catechol metabolite. The results from in vitro experiments with recombinant isoforms and P450 isoform-selective inhibitors suggested that the oxidative metabolism of lasofoxifene is catalyzed primarily by CYP3A and CYP2D6. In addition, its glucuronidation is catalyzed by UGTs that are expressed in both the liver (UGT1A1, UGT1A3, UGT1A6, and UGT1A9) and the intestine (UGT1A8 and UGT1A10).

A single-dose pharmacokinetic study of lasofoxifene in healthy volunteers and subjects with mild and moderate hepatic impairment.

Lasofoxifene, a selective estrogen receptor modulator for osteoporosis management, is metabolized primarily by hepatic oxidation and conjugation. This study compared the pharmacokinetics of 0.25 mg lasofoxifene in subjects with mild (Child-Pugh grade A, n = 6) or moderate (Child-Pugh grade B, n = 6) hepatic impairment and healthy volunteers (n = 6). Analysis of variance was used to calculate 90% confidence intervals for the ratios (impaired/healthy) of least squares mean log maximum plasma concentration (C(max)) and area under the curve (AUC) values. Lasofoxifene pharmacokinetics was similar between healthy and mild hepatic impairment subjects: ratios of C(max) and AUC from 0 to infinity (AUC([0-infinity])) were 101% (75.0-138) and 95.5% (77.9-117), respectively. In subjects with moderate hepatic impairment, ratios of C(max) and AUC([0-infinity]) were 121% (89.6-165) and 138% (112-169), respectively; mean terminal half-life was 252 hr compared to 193 hr in healthy subjects. Dose adjustment should not be required for subjects with mild to moderate hepatic impairment.

Effects of lasofoxifene on the pharmacokinetics and pharmacodynamics of single-dose warfarin.

AIM: To investigate the effect of steady-state lasofoxifene on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: Twelve healthy postmenopausal women received warfarin (single 20-mg dose) alone and during lasofoxifene. R- and S-warfarin concentrations, prothrombin time (PT) and international normalized ratio (INR) were determined with each treatment. RESULTS: Lasofoxifene had no clinically meaningful effect on R- or S-warfarin pharmacokinetics. The S-warfarin area under the plasma concentration-time curve (AUC) was 23% and 67% larger in subjects with *1/*2 and *1/*3 heterozygous mutations, relative to *1/*1, respectively. The mean PT AUC and Cmax ratio (90% confidence interval) was 91.9 (89.6, 94.2) and 84.2 (80.6, 87.8), respectively. INR results were similar. CONCLUSIONS: Lasofoxifene has no clinically meaningful effect on the pharmacokinetics of warfarin. Although the decrease in PT/INR may not be clinically meaningful, more frequent INR monitoring may be considered during lasofoxifene introduction and discontinuation, consistent with warfarin's label.

Effects of steady-state lasofoxifene on CYP2D6- and CYP2E1-mediated metabolism.

BACKGROUND: Lasofoxifene, a selective estrogen receptor modulator, may be coadministered with other drugs, raising the issue of drug-drug interactions. OBJECTIVE: Using a 7-day, open-label, sequential study to determine whether lasofoxifene at steady-state concentration affects cytochrome P450-mediated drug metabolism. METHODS: Lasofoxifene was tested in 18 postmenopausal women with probe drugs for CYP2E1 and CYP2D6. Changes in CYP2E1 metabolism were measured by the formation clearance of 6-hydroxychlorzoxazone (6-OHCLZ; Cl(f,6-OHCLZ)) following a 250 mg dose of chlorzoxazone in the absence (day 1) and presence (day 6) of lasofoxifene. Changes in the dextromethorphan/dextrorphan urine metabolic ratio (MRDX) measured the effect on CYP2D6 metabolism following a 30 mg dose of dextromethorphan in the absence and presence of lasofoxifene (days 2 and 7). RESULTS: Steady-state lasofoxifene did not affect the formation clearance of 6-OHCLZ or the urinary MRDX. For 6-OHCLZ, the lower boundary (87.12%) of the 90% confidence interval for the ratio (day 6/day 1) of Cl(f,6-OHCLZ) was well above the clinically acceptable ratio of 60%. Both the individual and group mean Cl(f,6-OHCLZ) values were comparable in the absence and presence of lasofoxifene. For MRDX, the upper boundary (129.37%) of the 90% confidence interval for the ratio (day 7/day 2) of MRDX was well below the stipulated ratio of 200%. The individual and mean MRDX values were comparable in the absence and presence of lasofoxifene. Lasofoxifene was well tolerated; adverse events were mild and transient. CONCLUSIONS: Lasofoxifene has no effect on CYP2E1- or CYP2D6-mediated drug metabolism and should not affect drugs metabolized by other cytochrome P450 isoenzymes.