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Research ArticleArticle

Bioavailability and Pharmacokinetics of Endoxifen in Female Rats and Dogs: Evidence to Support the Use of Endoxifen to Overcome the Limitations of CYP2D6-Mediated Tamoxifen Metabolism

Emily J. Koubek, Sarah A. Buhrow, Stephanie L. Safgren, Lee Jia, Matthew P. Goetz, Matthew M. Ames and Joel M. Reid
Drug Metabolism and Disposition February 2023, 51 (2) 183-192; DOI: https://doi.org/10.1124/dmd.122.000929

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    (A) Chemical structures of TAM and ENDX. Plasma profiles for (B) ENDX following intravenous administration of 2 mg/kg ENDX·HCl, (C) ENDX following oral administration of 40, 80, and 140 mg/kg ENDX·HCl, or (D) TAM and its major metabolites following oral administration of 80 mg/kg TAM to female Sprague-Dawley rats (n = 3 per dose group).

  • Fig. 2.
    Fig. 2.

    ENDX plasma concentrations 4 hours after oral administration of the specified doses to female Sprague-Dawley rats (n = 3 per dose group).

  • Fig. 3.
    Fig. 3.

    Plasma profiles for ENDX following oral administration of 2, 20, 80, and 200 mg/kg/kg ENDX·HCl to female Sprague-Dawley rats (n = 3 per dose group) on (A) day 1 and (B) day 28 of a 28-day daily dosing schedule.

  • Fig. 4.
    Fig. 4.

    Plasma profiles for (A) ENDX following intravenous administration of 0.5 mg/kg ENDX·HCl to fasted female beagle dogs, (B) ENDX following oral administration of 15, 30, and 100 mg/kg ENDX·HCl (day 1 on left, day 4 on right) to fasted female beagle dogs, (C) ENDX following oral administration of 100 mg/kg ENDX·HCl to fed female beagle dogs, or (D) TAM and ENDX following oral administration of 30 mg/kg TAM to fasted female beagle dogs (day 1 on left, day 4 on right). Dogs received daily oral administration of ENDX or TAM for 4 days (n = 2 per dose group).

  • Fig. 5.
    Fig. 5.

    Plasma profiles for ENDX following oral administration of (A) 5 mg/kg, (B) 15 mg/kg, and (C) 30 mg/kg ENDX·HCl to male and female beagle dogs on day 28 of a 28-day daily dosing schedule (n = 2 males and 2 females per dose group).

Tables

  • TABLE 1

    Single-dose pharmacokinetics of endoxifen and tamoxifen in rats

    EndoxifenTamoxifen
    I.V.P.O.P.O.
    Dose (mg/kg)22040801402008080
    FormulationHCl saltHCl saltHCl saltHCl saltHCl saltHCl saltFree BaseCitrate
    MetaboliteENDX4HTNDMTTAM
    Cmax (ng/mL)44135784511761569167614531873127638
    Tmax (h)42821226222
    Hlaf-Life (h)6.35.814.610.721.734.413.66222
    AUC0-24h (ng/mL*h)79050408500214002110030000238002811107246412027
    AUC0-∞ (ng/mL*h)8405590130003310039300954003620085521555153420459
    Vβ (L/kg)21.7
    CLapp (L/hr/kg)a2.393.583.082.403.562.102.21N/AN/AN/AN/A
    Absolute or relative bioavailability (%)677799671141082.39.220.5N/A

    • CLapp, apparent clearance; Tmax, time to reach maximum plasma concentration.

    • aFor intravenous doses, CLapp is Clp; for p.o. doses, CLapp is Cl/F.

    • bRelative bioavailability of TAM metabolites was calculated by dividing the AUC0-24h of the metabolite by the AUC0-24h of tamoxifen and multiplying by 100.

  • TABLE 2

    Twenty-eight–day multiple-dose pharmacokinetics of endoxifen in rats

    Dose (mg/kg)
    P.O.    		22080200
    Day 1
     Cmax (ng/mL)30.4453217521889
     C24h (ng/mL)7.58145.110761889
     Tmax (h)881224
     AUC0-24h (ng/mL*h)38081103130039600
     Half-life (h)5.814.69.8N/A
     Absolute Bioavailabilitya48%103%99%50%
    Day 28
     C0h14.57452213N/A
     Cmax (ng/mL)50.013053274N/A
     C24h (ng/mL)11.36081997N/A
     Tmax (h)184N/A
     AUC0-24h (ng/mL*h)6302220066200N/A
     Half-life (h)13.013.018.1N/A

    • C0h, plasma concentration at 0 hours; C24h, plasma concentration at 24 hours; N/A, not available; Tmax, time to reach maximum plasma concentration.

    • aAbsolute bioavailability was calculated using the following equation: ((AUC0-24)p.o. dose/(AUC0-24)I.V. dose) × ((2-mg/kg I.V. dose)/(p.o. dose mg/kg)) × 100%. The AUC0-24h estimate for the 2-mg/kg i.v. dose from the single-dose ENDX PK study in female rats (Table 1, 790 ng/mL*h).

  • TABLE 3

    Four-day multiple-dose pharmacokinetics of endoxifen in fasted and fed female beagle dogs

    RouteI.V.P.O.
    Dose (mg/kg)0.51530100100
    Fed/FastedFastedFed
    Dog I.D.5F98415F98451F98391F98422F98452F98463F98443F98476F98406F9849
    Day 1
     Cmax (ng/mL)633905211117172548390345271085045903250
     Half-life (h)7.65.83.18.313.89.18.97.38.37.2
     AUC0-24 (ng/mL*h)139289216189184811475138059491781702546937651100
     AUC0-∞ (ng/mL*h)1579892222372326221684467321344091968808055458395
     Clapp (L/h per kg)0.320.560.670.641.40.640.740.511.21.7
     Absolute bioavailabilityaN/AN/A59.462.129.162.854.479.779.723.6
    Day 4
     Cmax (ng/mL)228129825293889798604N/AN/AN/AN/A
     Half-life (h)4.812.229.28.15.810.2N/AN/AN/AN/A
     AUC0-24 (ng/mL*h)140635611805295148395880895N/AN/AN/AN/A
     AUC0-∞ (ng/mL*h)1453487296793487289818105027N/AN/AN/AN/A
     Clapp (L/h per kg)0.341.00.50.430.330.29N/AN/AN/AN/A
     Absolute bioavailabilityN/AN/A101117154180N/AN/AN/AN/A

    • AUC0-∞, area under the concentration-time curve from zero up to ∞ with extrapolation of the terminal phase; CLapp, apparent clearance; I.D., identification; N/A, not available.

    • aAbsolute bioavailability was calculated using the following equation: ((AUC0-∞)p.o. dose/(Avg. AUC0-∞)I.V. dose) × ((0.5-mg/kg i.v. dose)/(p.o. dose mg/kg)) × 100%.

  • TABLE 4

    Four-day multiple-dose pharmacokinetics of tamoxifen in fasted female beagle dogs

    Dose (mg/kg)
    P.O.    		30
    Dog I.D.4F98384F9848
    Day1414
    TAM
     Cmax (ng/mL)2286308316113505
     Tmax (h)4248
     Half-life14.11110.3566
     AUC0-24h (ng/mL*h)10913320941139167969
    ENDX
     Cmax (ng/mL)37927770137
     Tmax (h)40.5248
     Half-life194N/Cb9.2
     AUC0-24h (ng/mL*h)321729359062189
     Metabolite ratio (%)b29.59.18.03.2
    4HT
     Cmax (ng/mL)11201681937
     Tmax (h)411.58
     Half-life6.37.1N/CN/C
     AUC0-24h (ng/mL*h)49271228192.2436
     Metabolite ratio (%)45.23.81.70.6
    NDMT
     Cmax (ng/mL)68317203971166
     Tmax (h)441224
     Half-life1622233.6
     AUC0-24h (ng/mL*h)680424062702824289
     Metabolite ratio (%)a62.375.061.735.7

    • Tmax, time to reach the maximum plasma concentration; I.D., identification; N/C, not calculate.

    • aMetabolite ratio calculated by dividing the AUC0-24h of the metabolite by the AUC0-24h or tamoxifen and multiplying by 100.

    • bData did not allow for calculation.

  • TABLE 5

    Pharmacokinetics of endoxifen in male and female beagle dogs on day 28 following 28 days of daily dosing

    Dose (mg/kg) P.O.51015
    GenderMaleFemaleMaleFemaleMaleFemale
    Dog I.D.TZP-8TSP-8AGO-8XQO-8BFP-8XKP-8UJO-8UQO-8RTP-8AYP-8YRO-8YJO-8
    Cmax (ng/mL)4903303403505601050640630840133016302800
    Tmax (h)222424222242
    AUC0-24h (ng/mL*h)23401680191043506300123708540677010150172602166030760
    AUC0-72h (ng/mL*h)4110201034707300828016620166201174015090319702883061870

    • AUC0-72h, Area under the concentration-time curve from zero up to 72 hours; I.D., identification; Tmax, time to reach maximum plasma concentration.

Additional Files

  • Data Supplement

    • Supplemental Table -

      Supplemental Table 1. Four day multiple-dose pharmacokinetics of endoxifen in rats.

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Research ArticleArticle

Bioavailability and Pharmacokinetics of Endoxifen in Female Rats and Dogs

Emily J. Koubek, Sarah A. Buhrow, Stephanie L. Safgren, Lee Jia, Matthew P. Goetz, Matthew M. Ames and Joel M. Reid
Drug Metabolism and Disposition February 1, 2023, 51 (2) 183-192; DOI: https://doi.org/10.1124/dmd.122.000929
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