Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study
| Autor: | Mark L. Graham, William J. Irvin, Oludamilola Olajide, Karen E. Weck, Christine M. Walko, Sean Thomas Canale, Steven W. Corso, E. Claire Dees, Susan G. Moore, Rachel Elizabeth Raab, Lisa A. Carey, Wing Keung Chiu, Evan T. Ogburn, Howard L. McLeod, Steven M. Anderson, David A. Flockhart, James P. Evans, Joseph G. Ibrahim, Zeruesenay Desta, Kenneth J. Friedman, Jeffrey Peppercorn |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
CYP2D6 business.industry Metabolite Metabolism Pharmacology digestive system chemistry.chemical_compound Oncology Multicenter study chemistry Genotype Original Reports medicine Dosing skin and connective tissue diseases business hormones hormone substitutes and hormone antagonists Tamoxifen Active metabolite medicine.drug |
| Popis: | Purpose We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism. Patients and Methods One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later. Results As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (−0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still significantly lower. Conclusion This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients. |
| Databáze: | OpenAIRE |
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