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WOMEN'S HEALTH

Effects of Steady-State Lasofoxifene on CYP2D6- and CYP2E1-Mediated Metabolism

Clinical Director, Pfizer Worldwide Clinical Development, New York, NY

Jeannine M Fisher, MS

Senior Pharmacokinetic Associate, Pfizer Global Research and Development, Groton, CT

Ann E Taylor, MD

Associate Director, Pfizer Global Research and Development

Sheela Kolluri, PhD

Manager, Pfizer Global Research and Development

Mark J Gardner, PhD

Director, Pfizer Global Research and Development

R Scott Obach, PhD

Research Fellow, Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development

Robert L Walsky, BS

Senior Scientist, Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development

Reprints: Dr. Moller, Pfizer Worldwide Clinical Development, 235 E. 42nd St., MS 205/8/6, New York, NY 10017-5755, fax 212/308-0890, robert.a.moller{at}pfizer.com

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.

Key Words: chlorzoxazone, CYP2D6, CYP2E1, dextromethorphan, lasofoxifene

Published Online, December 20, 2005. www.theannals.com, DOI 10.1345/aph.1G347