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.
Moller
Robert A
RA
Pfizer Worldwide Clinical Development, New York, NY 10017-5755, USA. robert.a.moller@pfizer.com
Fisher
Jeannine M
JM
Taylor
Ann E
AE
Kolluri
Sheela
S
Gardner
Mark J
MJ
Obach
R Scott
RS
Walsky
Robert L
RL
D000284:Administration, Oral; D002753:Chlorzoxazone / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000652:urine; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D003915:Dextromethorphan / Q000097:blood / Q000494:pharmacology / Q000652:urine; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D004415:Dyspepsia / Q000139:chemically induced / Q000453:epidemiology; D005260:Female; D006801:Humans; D007297:Inpatients; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D017698:Postmenopause / Q000097:blood / Q000187:drug effects / Q000652:urine; D011759:Pyrrolidines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D012189:Retrospective Studies; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D011759:Pyrrolidines; D013764:Tetrahydronaphthalenes; C039289:6-hydroxychlorzoxazone; C111332:Lasofoxifene; D003915:Dextromethorphan; D019392:Cytochrome P-450 CYP2E1; D019389:Cytochrome P-450 CYP2D6; D002753:Chlorzoxazone