Effects of three cytochrome P450 inhibitors, ketoconazole, fluconazole, and paroxetine, on the pharmacokinetics of lasofoxifene.
OBJECTIVE
Two studies were conduced to assess the effects of ketoconazole, a CYP3A4/5 inhibitor; fluconazole, a CYP2C9 inhibitor; and paroxetine, a CYP2D6 inhibitor, on lasofoxifene pharmacokinetics.


METHODS
The first parallel group study was conducted in 45 healthy postmenopausal women (15 per group) to compare the pharmacokinetics of a single dose of lasofoxifene (0.25 mg) administered alone and in combination with ketoconazole (400 mg daily x 20 days) or fluconazole (400 mg daily x 20 days). Lasofoxifene was administered on day 2 and blood samples were collected serially for up to 456 h postdose (20 days). The second study enrolled 20 healthy postmenopausal women (10 per group) to compare the pharmacokinetics of a single dose of lasofoxifene (0.25 mg) alone and in combination with paroxetine (30 mg qd x 21 days). Lasofoxifene was given on day 8 of paroxetine treatment and blood samples were collected serially for up to 336 h postdose.


RESULTS
All subjects completed the study and the treatments were well tolerated. Lasofoxifene C(max) and AUC ratios [90% confidence interval (CI)] with/without ketoconazole were 111% (98.4, 127) and 120% (105, 136), respectively, and were 91.3% (80.3, 104) and 104% (91.4, 118), respectively, with/without fluconazole. Lasofoxifene C(max) and AUC ratios (90% CI) with/without paroxetine were 118% (95.4, 146) and 135% (120, 152), respectively.


CONCLUSIONS
Coadministration of potent inhibitors of CYP3A4/5 and CYP2D6, but not CYP2C9, resulted in a moderate increase in lasofoxifene exposure. No dosage adjustment should be required when lasofoxifene is coadministered with ketoconazole, fluconazole, paroxetine or other agents that inhibit these CYP enzymes.
Ouellet
D
D
Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. daniele.ouellet@pfizer.com
Bramson
C
C
Roman
D
D
Remmers
A E
AE
Randinitis
E
E
Milton
A
A
Gardner
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008875:Middle Aged; D017374:Paroxetine / Q000008:administration & dosage / Q000494:pharmacology*; D017698:Postmenopause; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics*
D018687:Antidepressive Agents, Second-Generation; D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D011759:Pyrrolidines; D013764:Tetrahydronaphthalenes; C111332:Lasofoxifene; D017374:Paroxetine; D015725:Fluconazole; D007654:Ketoconazole