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.
  • 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.

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

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
  • 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 large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel

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
    • Concentrations used exceed those found in vivo following normal therapeutic doses
  • 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.

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.

 

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.

  • 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.

PK of ABRAXANE (260 mg/m2 over 30 minutes) vs paclitaxel injection (175 mg/m2over 3 hours)

  • ABRAXANE clearance was 43% larger than paclitaxel injection
  • ABRAXANE has a 53% higher volume of distribution than paclitaxel injection
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
  • 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 large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel
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
    • Concentrations used exceed those found in vivo following normal therapeutic doses
  • 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.

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.

INDICATIONS

ABRAXANE is indicated for:

  • The treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated
  • The first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy
  • The first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine

INDICATIONS

ABRAXANE is indicated for:

  • The treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated
  • The first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy
  • The first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine