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Pharmacokinetics of endoxifen and tamoxifen in female mice: implications for comparative in vivo activity studies.

ABSTRACT: Reduced CYP2D6 metabolism and low Z-endoxifen (ENDX) concentrations may increase the risk of breast cancer recurrence in tamoxifen (TAM)-treated women. Little is known regarding the differences between TAM and ENDX murine pharmacokinetics or the effect of administration route on plasma concentrations of each drug.The pharmacokinetics of TAM and ENDX were characterized in female mice.For subcutaneous [s.c.] and oral TAM (4, 10 and 20 mg/kg), TAM AUC increased in a linear manner, but concentrations of the active metabolites [ENDX and 4-hydroxytamoxifen (4HT)] remained low. For oral TAM (20 mg), 4HT concentrations were tenfold greater (>25 ng/ml) than achievable in TAM-treated humans. Both oral (10-200 mg/kg) and s.c. (2.5-25 mg/kg) ENDX·HCl resulted in a greater than dose-proportional increase in AUC, with eightfold greater ENDX concentrations than an equivalent TAM dose. ENDX accumulated in plasma after 5-day dosing of 25 or 100 mg/kg ENDX·HCl and exceeded target concentrations of 0.1 and 1.0 ?M, respectively, by twofold to fourfold.In murine models, oral ENDX yields substantially higher ENDX concentrations, compared to TAM. The low 4HT and ENDX concentrations observed in mice receiving s.c. TAM mirror the TAM pharmacokinetics in humans with impaired CYP2D6 metabolism. These data support the ongoing development of ENDX as a novel agent for the endocrine treatment of ER-positive breast cancer.

SUBMITTER: Reid JM

PROVIDER: S-EPMC4343319 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Pharmacokinetics of endoxifen and tamoxifen in female mice: implications for comparative in vivo activity studies.

Reid Joel M JM Goetz Matthew P MP Buhrow Sarah A SA Walden Chad C Safgren Stephanie L SL Kuffel Mary J MJ Reinicke Kathryn E KE Suman Vera V Haluska Paul P Hou Xiaonan X Ames Matthew M MM

Cancer chemotherapy and pharmacology 20141016 6

<h4>Background</h4>Reduced CYP2D6 metabolism and low Z-endoxifen (ENDX) concentrations may increase the risk of breast cancer recurrence in tamoxifen (TAM)-treated women. Little is known regarding the differences between TAM and ENDX murine pharmacokinetics or the effect of administration route on plasma concentrations of each drug.<h4>Methods</h4>The pharmacokinetics of TAM and ENDX were characterized in female mice.<h4>Results</h4>For subcutaneous [s.c.] and oral TAM (4, 10 and 20 mg/kg), TAM ...[more]

PMID: 25318936

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Project description:BackgroundPolymorphic CYP2D6 is primarily responsible for metabolic activation of tamoxifen to endoxifen. We previously reported that by increasing the daily tamoxifen dose to 40 mg/day in CYP2D6 intermediate metabolizer (IM), but not poor metabolizer (PM), patients achieve endoxifen concentrations similar to those of extensive metabolizer patients on 20 mg/day. We expanded enrollment to assess the safety of CYP2D6 genotype-guided dose escalation and investigate concentration differences between races.MethodsPM and IM breast cancer patients currently receiving tamoxifen at 20 mg/day were enrolled for genotype-guided escalation to 40 mg/day. Endoxifen was measured at baseline and after 4 months. Quality-of-life data were collected using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and Breast Cancer Prevention Trial Menopausal Symptom Scale at baseline and after 4 months.ResultsIn 353 newly enrolled patients, genotype-guided dose escalation eliminated baseline concentration differences in IM (p = .08), but not PM (p = .009), patients. Endoxifen concentrations were similar in black and white patients overall (p = .63) and within CYP2D6 phenotype groups (p > .05). In the quality-of-life analysis of 480 patients, dose escalation did not meaningfully diminish quality of life; in fact, improvements were seen in several measures including the FACT Breast Cancer subscale (p = .004) and limitations in range of motion (p < .0001) in IM patients.ConclusionDifferences in endoxifen concentration during treatment can be eliminated by doubling the tamoxifen dose in IM patients, without an appreciable effect on quality of life. Validation of the association between endoxifen concentration and efficacy or prospective demonstration of improved efficacy is necessary to warrant clinical uptake of this personalized treatment strategy.Implications for practiceThis secondary analysis of a prospective CYP2D6 genotype-guided tamoxifen dose escalation study confirms that escalation to 40 mg/day in patients with low-activity CYP2D6 phenotypes (poor or intermediate metabolizers) increases endoxifen concentrations without any obvious increases in treatment-related toxicity. It remains unknown whether endoxifen concentration is a useful predictor of tamoxifen efficacy, and thus, there is no current role in clinical practice for CYP2D6 genotype-guided tamoxifen dose adjustment. If future studies confirm the importance of endoxifen concentrations for tamoxifen efficacy and report a target concentration, this study provides guidance for a dose-adjustment approach that could maximize efficacy while maintaining patient quality of life.

Project description:The tamoxifen-inducible Cre-loxP system is widely used to overcome gene targeting pre-adult lethality, to modify a specific cell population at desired time-points, and to visualize and trace cells in fate-mapping studies. In this study we focused on tamoxifen degradation kinetics, because for all genetic fate-mapping studies, the period during which tamoxifen or its metabolites remain active in the CNS, is essential. Additionally, we aimed to define the tamoxifen administration scheme, enabling the maximal recombination rate together with minimal animal mortality. The time window between tamoxifen injection and the beginning of experiments should be large enough to allow complete degradation of tamoxifen and its metabolites. Otherwise, these substances could promote an undesired recombination, leading to data misinterpretation. We defined the optimal time window, allowing the complete degradation of tamoxifen and its metabolites, such as 4-hydroxytamoxifen, N-desmethyltamoxifen, endoxifen and norendoxifen, in the mouse brain after intraperitoneal tamoxifen injection. We determined the biological activity of these substances in vitro, as well as a minimal effective concentration of the most potent metabolite 4-hydroxytamoxifen causing recombination in vivo. For this purpose, we analyzed the recombination rate in double transgenic Cspg4-cre/Esr1/ROSA26Sortm14(CAG-tdTomato) mice, in which tamoxifen administration triggers the expression of red fluorescent protein in NG2-expressing cells, and employed a liquid chromatography, coupled with mass spectrometry, to determine the concentration of studied substances in the brain. We determined the degradation kinetics of these substances, and revealed that this process is influenced by mouse strains, age of animals, and dosage. Our results revealed that tamoxifen and its metabolites were completely degraded within 8 days in young adult C57BL/6J mice, while the age-matched FVB/NJ male mice displayed more effective degradation. Moreover, aged C57BL/6J mice were unable to metabolize all substances within 8 days. The lowering of initial tamoxifen dose leads to a significantly faster degradation of all studied substances. A disruption of the blood-brain barrier caused no concentration changes of any tamoxifen metabolites in the ipsilateral hemisphere. Taken together, we showed that tamoxifen metabolism in mouse brains is age-, strain- and dose-dependent, and these factors should be taken into account in the experimental design.

Dataset Information

Pharmacokinetics of endoxifen and tamoxifen in female mice: implications for comparative in vivo activity studies.

Publications

Pharmacokinetics of endoxifen and tamoxifen in female mice: implications for comparative in vivo activity studies.

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