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BACKGROUND.Mastocytosis is characterized by the abnormal proliferation of mast cells in 1 or more organs. In most patients, a mutation is present in the gene for C-KIT, resulting in deregulation of the c-kit receptor. Imatinib mesylate is a potent inhibitor of c-kit receptor tyrosine kinase activity. Therefore, the authors evaluated the efficacy and safety of imatinib mesylate as treatment for patients with systemic mastocytosis. METHODS.Patients with systemic mastocytosis received imatinib mesylate orally at a dose of 400 mg once daily for 3 to 6 months. Low doses of prednisone were added during the first 2 weeks. Endpoints were reductions in serum tryptase, urinary N-methylhistamine excretion, skin lesions, the number of mast cells in bone marrow sections, hepatomegaly and/or splenomegaly, and symptoms. RESULTS.Of 14 patients who were included in the study, 11 patients had the D816V mutation. One patient expressed the FIP1L1-PDGFR-a rearrangement gene. In 2 patients, no mutation was found. In 10 patients, serum tryptase levels decreased >20%. In all patients, urinary N-methylhistamine excretion was reduced. In 8 of 13 evaluable patients, the number of mast cells in the bone marrow decreased. Skin symptoms diminished in 5 of 9 patients. Hepatosplenomegaly improved in 3 of 6 patients. Symptoms decreased in 8 of 13 patients. In all patients who had the D816V mutation, reductions in !2 endpoints were achieved. In the patient who expressed the FIP1L1-PDGFR-a rearrangement gene, a complete response was attained. In general, imatinib mesylate was tolerated well. CONCLUSIONS.Imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation.

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Background and ObjectiveThe anti-oestrogen tamoxifen requires metabolic activation to endoxifen by cytochrome P450 (CYP) enzymes, predominantly CYP2D6. Potent CYP2D6-inhibiting antidepressants can seriously disrupt tamoxifen metabolism, probably influencing the efficacy of tamoxifen. For this reason, paroxetine and fluoxetine are recommended not to be used with tamoxifen in breast cancer patients. We investigated the effects of switching potent CYP2D6-inhibiting antidepressants to weak CYP2D6-inhibiting antidepressants on the plasma pharmacokinetics of tamoxifen.MethodsTen breast cancer patients who were treated with tamoxifen in combination with a potent CYP2D6-inhibiting antidepressant (paroxetine or fluoxetine) for at least 4 weeks were enrolled. Under close supervision by a psychiatrist, patients were switched to treatment with escitalopram or venlafaxine (weak CYP2D6-inhibiting antidepressants). Before and after the switch, pharmacokinetic blood sampling was performed over 24 h. Pharmacokinetic parameters were estimated using noncompartmental analysis. Adverse effects were recorded during the study.ResultsEndoxifen exposure was ~3-fold higher during escitalopram co-administration than during paroxetine or fluoxetine co-administration (median 387 nM·h [range 159–637 nM·h] versus 99.2 nM·h [range 70.0–210 nM·h]; P = 0.012; Wilcoxon signed-rank test). The ratio of endoxifen to N-desmethyltamoxifen and the ratio of 4-hydroxytamoxifen to tamoxifen increased by 3.3- and ~1.5-fold, reflecting increased CYP2D6 activity. Antidepressant switching did not result in psychiatric problems or antidepressant-related adverse effects.ConclusionIn this study, switching to the weak CYP2D6 inhibitor escitalopram was safe and feasible and resulted in clinically relevant rises in endoxifen concentrations. We therefore advise switching paroxetine and fluoxetine to escitalopram in patients using tamoxifen. However, switching should always be weighed in individual patients.

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