PHARMACOKINETICS

  • Absorption

    The pharmacokinetics (PK) of total paclitaxel following 30- and 180-minute infusions of ABRAXANE at dose levels of 80 to 375 mg/m2 were determined in clinical studies.

    The pharmacokinetics (PK) of total paclitaxel following 30- and 180-minute infusions of ABRAXANE at dose levels of 80 to 375 mg/m2 were determined in clinical studies.

    • Following intravenous administration of ABRAXANE, paclitaxel plasma concentrations declined in a biphasic manner
      • The initial rapid decline represents distribution to the peripheral compartment
      • The slower second phase represented drug elimination

    The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m2, and the PK of paclitaxel for ABRAXANE were independent of the duration of intravenous administration.

    The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m2, and the PK of paclitaxel for ABRAXANE were independent of the duration of intravenous administration.

    PK of ABRAXANE (260 mg/m2 over 30 minutes) vs paclitaxel injection (175 mg/m2 over 3 hours)

    PK of ABRAXANE (260 mg/m2 over 30 minutes) vs paclitaxel injection (175 mg/m2 over 3 hours)

    • ABRAXANE clearance was 43% larger than paclitaxel injection
    • ABRAXANE has a 53% higher volume of distribution than paclitaxel injection
    CLOSE THE TAB
  • Distribution

    Following ABRAXANE administration to patients with solid tumors, paclitaxel is evenly distributed into blood cells and plasma and is highly bound to plasma proteins (94%).

    In a within‑patient comparison study, the fraction of unbound paclitaxel in plasma was significantly higher with ABRAXANE (6.2%) than with solvent‑based paclitaxel (2.3%).

    • This contributes to significantly higher exposure to unbound paclitaxel with ABRAXANE compared with solvent‑based paclitaxel, when the total exposure is comparable

    In vitro studies demonstrating the binding qualities of ABRAXANE using paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicate that

    In vitro studies demonstrating the binding qualities of ABRAXANE using paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicate that

    • The presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel

    The total volume of distribution is approximately 1741 L

    The total volume of distribution is approximately 1741 L

    • The large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel
    CLOSE THE TAB
  • Metabolism

    In vitro studies with human liver microsomes showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by CYP2C8, and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6α,3’-p-dihydroxypaclitaxel, by CYP3A4.

    In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents

    • Ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporine, teniposide, etoposide, and vincristine
    • Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8

    The PK of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4.

    The PK of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4.

    CLOSE THE TAB
  • Elimination

    At the clinical dose range of 80 to 300 mg/m2, the mean total clearance of paclitaxel ranges from 13 to 30 L/h/m2, and the mean terminal half-life ranges from 13 to 27 hours.

    After a 30-minute infusion of 260 mg/m2 dose of ABRAXANE, the mean value for cumulative urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1% of the total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3’-p-hydroxypaclitaxel.

    Fecal excretion was approximately 20% of the total dose administered.

    CLOSE THE TAB
  • Absorption

    The pharmacokinetics (PK) of total paclitaxel following 30- and 180-minute infusions of ABRAXANE at dose levels of 80 to 375 mg/m2 were determined in clinical studies.

    The pharmacokinetics (PK) of total paclitaxel following 30- and 180-minute infusions of ABRAXANE at dose levels of 80 to 375 mg/m2 were determined in clinical studies.

    • Following intravenous administration of ABRAXANE, paclitaxel plasma concentrations declined in a biphasic manner
      • The initial rapid decline represents distribution to the peripheral compartment
      • The slower second phase represented drug elimination

    The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m2, and the PK of paclitaxel for ABRAXANE were independent of the duration of intravenous administration.

    The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m2, and the PK of paclitaxel for ABRAXANE were independent of the duration of intravenous administration.

    PK of ABRAXANE (260 mg/m2 over 30 minutes) vs paclitaxel injection (175 mg/m2 over 3 hours)

    PK of ABRAXANE (260 mg/m2 over 30 minutes) vs paclitaxel injection (175 mg/m2 over 3 hours)

    • ABRAXANE clearance was 43% larger than paclitaxel injection
    • ABRAXANE has a 53% higher volume of distribution than paclitaxel injection
    CLOSE THE TAB
  • Distribution

    Following ABRAXANE administration to patients with solid tumors, paclitaxel is evenly distributed into blood cells and plasma and is highly bound to plasma proteins (94%).

    In a within‑patient comparison study, the fraction of unbound paclitaxel in plasma was significantly higher with ABRAXANE (6.2%) than with solvent‑based paclitaxel (2.3%).

    • This contributes to significantly higher exposure to unbound paclitaxel with ABRAXANE compared with solvent‑based paclitaxel, when the total exposure is comparable

    In vitro studies demonstrating the binding qualities of ABRAXANE using paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicate that

    In vitro studies demonstrating the binding qualities of ABRAXANE using paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicate that

    • The presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel

    The total volume of distribution is approximately 1741 L

    The total volume of distribution is approximately 1741 L

    • The large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel
    CLOSE THE TAB
  • Metabolism

    In vitro studies with human liver microsomes showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by CYP2C8, and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6α, 3’-p-dihydroxypaclitaxel, by CYP3A4.

    In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents

    • Ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporine, teniposide, etoposide, and vincristine
    • Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8

    The PK of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4.

    The PK of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4.

    CLOSE THE TAB
  • Elimination

    At the clinical dose range of 80 to 300 mg/m2, the mean total clearance of paclitaxel ranges from 13 to 30 L/h/m2, and the mean terminal half-life ranges from 13 to 27 hours.

    After a 30-minute infusion of 260 mg/m2 dose of ABRAXANE, the mean value for cumulative urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1% of the total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3’-p-hydroxypaclitaxel.

    Fecal excretion was approximately 20% of the total dose administered.

    At the clinical dose range of 80 to 300 mg/m2, the mean total clearance of paclitaxel ranges from 13 to 30 L/h/m2, and the mean terminal half-life ranges from 13 to 27 hours.

    After a 30-minute infusion of 260 mg/m2 dose of ABRAXANE, the mean value for cumulative urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1% of the total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3’-p-hydroxypaclitaxel.

    Fecal excretion was approximately 20% of the total dose administered.

    CLOSE THE TAB
YOU ARE NOW LEAVING www.abraxanepro.com
Additional Information for Readers Provided by Celgene Corporation

The clinical trial described in this article served as the
basis for the approval for ABRAXANE for Injectable Suspension.
The analyses contained in the article may differ from those in the package insert for ABRAXANE.

Please see Important Safety Information and Prescribing Information, including Boxed WARNING.

Click “OK” to proceed or “CANCEL” to return to
www.abraxanepro.com

OK
CANCEL