Effects of three cytochrome P450 inhibitors, ketoconazole, fluconazole, and paroxetine, on the pharmacokinetics of lasofoxifene

Abstract

AimsTwo 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. MethodsThe 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 × 20 days) or fluconazole (400 mg daily × 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 × 21 days). Lasofoxifene was given on day 8 of paroxetine treatment and blood samples were collected serially for up to 336 h postdose. ResultsAll 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. ConclusionsCoadministration 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.

Disposition of Lasofoxifene, a Next-Generation Selective Estrogen Receptor Modulator, in Healthy Male Subjects

“…Because oxidation accounts for about half of total lasofoxifene clearance and this pathway is further divided among multiple P450 isozymes, inhibition of a single enzyme will not have a clinically significant impact on the pharmacokinetics of lasofoxifene. Phase 2 clinical studies showed only modest increase in both the AUC and C max of lasofoxifene with concomitant administration of either ketoconazole, a potent inhibitor of CYP3A4 (Ouellet et al, 2006), or paroxetine, a potent inhibitor of CYP2D6 (Ouellet et al, 2006). Considering the large safety margin for lasofoxifene, no dosage adjustment is needed when coadministered with either CYP3A or CYP2D6 inhibitors (Ouellet et al, 2006).…”

“…Phase 2 clinical studies showed only modest increase in both the AUC and C max of lasofoxifene with concomitant administration of either ketoconazole, a potent inhibitor of CYP3A4 (Ouellet et al, 2006), or paroxetine, a potent inhibitor of CYP2D6 (Ouellet et al, 2006). Considering the large safety margin for lasofoxifene, no dosage adjustment is needed when coadministered with either CYP3A or CYP2D6 inhibitors (Ouellet et al, 2006). However, as a result of these data, there is the potential for drug-drug interactions with any coadministered drug that is also eliminated by the same metabolic pathways, particularly those involving phase I oxidation by microsomal P450 enzymes.…”

Lasofoxifene for the prevention and treatment of postmenopausal osteoporosis

“…Administration of loading doses resulted in reaching steady-state concentrations within approximately seven to nine days. The pharmacokinetics of lasofoxifene are linear over a wide dose-range (0.01 to 100 mg)57 and are not significantly affected by age, ethnicity, weight, moderately impaired hepatic or renal function, or medications such as warfarin, ketoconazole, and digoxin 60–63. In a study of lasofoxifene disposition in healthy male subjects, it was eliminated by phase I oxidative metabolism (largely mediated by CYP2D6 and CYP3A4) and phase II conjugation 64…”

In vitro and in vivo evaluation of cucurbitacin E on rat hepatic CYP2C11 expression and activity using LC-MS/MS

“…Fluconazole (60 mg kg 1 , i.p.) was used as a positive control for enzyme inhibition studies [25]. For the 3 d treatments, rats were pre-treated with CuE (50-200 µg kg 1 day 1 , i.p.)…”

“…To determine the mechanism of CuE inhibition of tolbutamide 4-hydroxylase, a range of tolbutamide (25,50,75, 100 µmol L 1 ) and CuE (5, 10, 25, 50 µmol L 1 ) concentrations were used for inhibition kinetics studies. Sulfaphenazole (5-50 µmol L 1 ), a selective rat CYP2C11 inhibitor, was used as a positive control [21,22].…”