Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Following intravenous administration of paclitaxel, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.
Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of paclitaxel at dose levels of 135 and 175 mg/m2 were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table:
Dose | Infusion | N | Cmax | AUC (0-∞) | T-HALF | CLT |
135 | 24 | 2 | 195 | 6300 | 52.7 | 21.7 |
175 | 24 | 4 | 365 | 7993 | 15.7 | 23.8 |
135 | 3 | 7 | 2170 | 7952 | 13.1 | 17.7 |
175 | 3 | 5 | 3650 | 15007 | 20.2 | 12.2 |
Cmax = Maximum plasma concentration AUC (0-∞) = Area under the plasma concentration-time curve from time 0 to infinity CLT = Total body clearance | ||||||
It appeared that with the 24-hour infusion of paclitaxel, a 30% increase in dose (135 mg/m2 versus 175 mg/m2) increased the Cmax by 87%, whereas the AUC (0-∞) remained proportional. However, with a 3-hour infusion, for a 30% increase in dose, the Cmax and AUC (0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state, with the 24-hour infusion of paclitaxel, ranged from 227 to 688 L/m2, indicating extensive extravascular distribution and/or tissue binding of paclitaxel.
The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses of 15-135 mg/m2 given by 1-hour infusions (n=15), 30-275 mg/m2 given by 6-hour infusions (n=36), and 200-275 mg/m2 given by 24-hour infusions (n=54) in Phase 1 & 2 studies. Values for CLT and volume of distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of paclitaxel in patients with AIDS-related Kaposi’s sarcoma have not been studied.
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicate that between 89%-98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.
After intravenous administration of 15-275 mg/m2 doses of Paclitaxel Injection, USP as 1-, 6-, or 24-hour infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance. In five patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Total recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6α-hydroxypaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6α, 3’-p-dihydroxy-paclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics 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. (See PRECAUTIONS: Drug Interactions section.)
The disposition and toxicity of paclitaxel 3-hour infusion were evaluated in 35 patients with varying degrees of hepatic function. Relative to patients with normal bilirubin, plasma paclitaxel exposure in patients with abnormal serum bilirubin ≤2 times upper limit of normal (ULN) administered 175 mg/m2 was increased, but with no apparent increase in the frequency or severity of toxicity. In 5 patients with serum total bilirubin >2 times ULN, there was a statistically nonsignificant higher incidence of severe myelosuppression, even at a reduced dose (110 mg/m2), but no observed increase in plasma exposure. (See PRECAUTIONS: Hepatic and DOSAGE AND ADMINISTRATION.) The effect of renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated.
Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.
Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Following intravenous administration of paclitaxel, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.
Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of paclitaxel at dose levels of 135 and 175 mg/m2 were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table:
Dose | Infusion | N | Cmax | AUC (0-∞) | T-HALF | CLT |
135 | 24 | 2 | 195 | 6300 | 52.7 | 21.7 |
175 | 24 | 4 | 365 | 7993 | 15.7 | 23.8 |
135 | 3 | 7 | 2170 | 7952 | 13.1 | 17.7 |
175 | 3 | 5 | 3650 | 15007 | 20.2 | 12.2 |
Cmax = Maximum plasma concentration AUC (0-∞) = Area under the plasma concentration-time curve from time 0 to infinity CLT = Total body clearance | ||||||
It appeared that with the 24-hour infusion of paclitaxel, a 30% increase in dose (135 mg/m2 versus 175 mg/m2) increased the Cmax by 87%, whereas the AUC (0-∞) remained proportional. However, with a 3-hour infusion, for a 30% increase in dose, the Cmax and AUC (0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state, with the 24-hour infusion of paclitaxel, ranged from 227 to 688 L/m2, indicating extensive extravascular distribution and/or tissue binding of paclitaxel.
The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses of 15-135 mg/m2 given by 1-hour infusions (n=15), 30-275 mg/m2 given by 6-hour infusions (n=36), and 200-275 mg/m2 given by 24-hour infusions (n=54) in Phase 1 & 2 studies. Values for CLT and volume of distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of paclitaxel in patients with AIDS-related Kaposi’s sarcoma have not been studied.
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicate that between 89%-98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.
After intravenous administration of 15-275 mg/m2 doses of Paclitaxel Injection, USP as 1-, 6-, or 24-hour infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance. In five patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Total recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6α-hydroxypaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6α, 3’-p-dihydroxy-paclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics 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. (See PRECAUTIONS: Drug Interactions section.)
The disposition and toxicity of paclitaxel 3-hour infusion were evaluated in 35 patients with varying degrees of hepatic function. Relative to patients with normal bilirubin, plasma paclitaxel exposure in patients with abnormal serum bilirubin ≤2 times upper limit of normal (ULN) administered 175 mg/m2 was increased, but with no apparent increase in the frequency or severity of toxicity. In 5 patients with serum total bilirubin >2 times ULN, there was a statistically nonsignificant higher incidence of severe myelosuppression, even at a reduced dose (110 mg/m2), but no observed increase in plasma exposure. (See PRECAUTIONS: Hepatic and DOSAGE AND ADMINISTRATION.) The effect of renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated.
Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.
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