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Paclitaxelum Accord Actions |
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Paclitaxelum Accord is an anticancer agent from the taxane class of drugs.
Pharmacology: Paclitaxelum Accord is an antimicrotubule antineoplastic agent. It promotes microtubule assembly by enhancing the polymerisation of tubulin, the protein subunit of spindle microtubules, even in the absence of the mediators normally required for microtubule assembly [e.g. guanosine triphosphate (GTP)], thereby inducing the formation of stable, nonfunctional microtubules. While the precise mechanism of action of the drug is not completely known, Paclitaxelum Accord disrupts the dynamic equilibrium within the microtubule system and blocks cells in the late G2 phase and M phase of the cell cycle, inhibiting cell replication and impairing function of nervous tissue.
Pharmacokinetics: After Paclitaxelum Accord is administered intravenously, its plasma concentration declines biphasically. The first phase shows rapid decline representing distribution of Paclitaxelum Accord to the peripheral compartment and elimination. This initial phase is followed by a relatively slow elimination of Paclitaxelum Accord from the peripheral compartment.
The following ranges for the pharmacokinetic parameters have been determined in patients given doses of 135 and 175 mg/m2 as 3 hour and 24 hour infusions of Paclitaxelum Accord: Mean terminal half-life: 3 to 52.7 hours; total body clearance: 11.6 to 24 L/h/m2; mean steady-state volume of distribution: 198 to 688 L/m2.
These indicate extensive distribution of Paclitaxelum Accord outside the vascular system and/or tissue binding.
The following mean values for the pharmacokinetic parameters have been reported following a 3 hour infusion of 175 mg/m2 Paclitaxelum Accord: Mean terminal half-life: 9.9 hours; mean total body clearance: 12.4 L/h/m2.
The serum protein-binding of Paclitaxelum Accord is 89%.
The liver is thought to be the primary site of metabolism for Paclitaxelum Accord. The mean cumulative urinary recovery of unchanged Paclitaxelum Accord has been reported as 1.8 to 12.6% of the dose.
Paclitaxelum Accord is injected into a vein through an IV. A healthcare provider will give you this injection. You may be given other medications to prevent an allergic reaction while you are receiving Paclitaxelum Accord.
Paclitaxelum Accord is usually given once every 3 weeks. Follow your doctor's dosing instructions very carefully.
Your breathing, blood pressure, oxygen levels, kidney function, and other vital signs will be watched closely while you are receiving Paclitaxelum Accord.
Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when Paclitaxelum Accord is injected.
Paclitaxelum Accord can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.
Paclitaxelum Accord protein-bound is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. Paclitaxelum Accord protein-bound must be given slowly, and the IV infusion can take at least 30 minutes to complete.
Paclitaxelum Accord protein-bound is usually given once every 3 weeks. Follow your doctor's dosing instructions very carefully.
Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when Paclitaxelum Accord protein-bound is injected.
To make sure this medication is helping your condition and not causing harmful effects, your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests. Do not miss any follow-up visits to your doctor.
Paclitaxelum Accord is a microtubule inhibitor 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. Paclitaxelum Accord induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Absorption
The pharmacokinetics of total Paclitaxelum Accord following 30 and 180-minute infusions of Paclitaxelum Accord at dose levels of 80 to 375 mg/m2 were determined in clinical studies. Dose levels of mg/m2 refer to mg of Paclitaxelum Accord in Paclitaxelum Accord. Following intravenous administration of Paclitaxelum Accord, Paclitaxelum Accord plasma concentrations declined in a biphasic manner, the initial rapid decline representing distribution to the peripheral compartment and the slower second phase representing drug elimination.
The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m2 and the pharmacokinetics of Paclitaxelum Accord for Paclitaxelum Accord were independent of the duration of intravenous administration.
The pharmacokinetic data of 260 mg/m2 Paclitaxelum Accord administered over a 30-minute infusion was compared to the pharmacokinetics of 175 mg/m2 Paclitaxelum Accord injection over a 3-hour infusion. Clearance was larger (43%) and the volume of distribution was higher (53%) for Paclitaxelum Accord than for Paclitaxelum Accord injection. There were no differences in terminal half-lives.
Distribution
Following Paclitaxelum Accord administration to patients with solid tumors, Paclitaxelum Accord 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 Paclitaxelum Accord in plasma was significantly higher with Paclitaxelum Accord (6.2%) than with solvent-based Paclitaxelum Accord (2.3%). This contributes to significantly higher exposure to unbound Paclitaxelum Accord with Paclitaxelum Accord compared with solvent-based Paclitaxelum Accord, when the total exposure is comparable. In vitro studies of binding to human serum proteins, using Paclitaxelum Accord concentrations ranging from 0.1 to 50 µg/mL, indicated that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of Paclitaxelum Accord. The total volume of distribution is approximately 1741 L; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of Paclitaxelum Accord.
Metabolism
In vitro studies with human liver microsomes and tissue slices showed that Paclitaxelum Accord 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 Paclitaxelum Accord 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 Paclitaxelum Accord 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 Paclitaxelum Accord 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 doses of Paclitaxelum Accord, the mean values 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.
Specific Populations
Pharmacokinetics in Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of Paclitaxelum Accord following Paclitaxelum Accord administration was studied in patients with advanced solid tumors. The results showed that mild hepatic impairment (total bilirubin >1 to ≤1.5 x ULN, AST ≤10 x ULN, n=8) had no clinically important effect on pharmacokinetics of Paclitaxelum Accord. Patients with moderate (total bilirubin >1.5 to ≤ 3 x ULN, AST ≤10 x ULN, n=7) or severe (total bilirubin >3 to ≤5 x ULN, n=5) hepatic impairment had a 22% to 26% decrease in the maximum elimination rate of Paclitaxelum Accord and approximately 20% increase in mean Paclitaxelum Accord AUC compared with patients with normal hepatic function (total bilirubin ≤ULN, AST ≤ULN, n=130)..
Elimination of Paclitaxelum Accord shows an inverse correlation with total bilirubin and a positive correlation with serum albumin. Pharmacokinetic/pharmacodynamic modeling indicates that there is no correlation between hepatic function (as indicated by the baseline albumin or total bilirubin level) and neutropenia after adjusting for Paclitaxelum Accord exposure. Pharmacokinetic data are not available for patients with total bilirubin >5 x ULN or for patients with metastatic adenocarcinoma of the pancreas.
Pharmacokinetics in Renal Impairment
The effect of pre-existing mild (creatinine clearance ≥60 to <90 mL/min, n=61) or moderate (creatinine clearance ≥30 to <60 mL/min, n=23) renal impairment on the pharmacokinetics of Paclitaxelum Accord following Paclitaxelum Accord administration was studied in patients with advanced solid tumors. Mild to moderate renal impairment had no clinically important effect on the maximum elimination rate and systemic exposure (AUC and Cmax) of Paclitaxelum Accord.
Other Intrinsic Factors
Population pharmacokinetic analyses for Paclitaxelum Accord show that body weight (40 to 143 kg), body surface area (1.3 to 2.4 m2), gender, race (Asian vs. White), age (24 to 85 years) and type of solid tumors do not have a clinically important effect on the maximum elimination rate and systemic exposure (AUC and Cmax) of Paclitaxelum Accord.
Pharmacokinetic Interactions between Paclitaxelum Accord and Carboplatin
Administration of carboplatin immediately after the completion of the Paclitaxelum Accord infusion to patients with NSCLC did not cause clinically meaningful changes in Paclitaxelum Accord exposure. The observed mean AUCinf of free carboplatin was approximately 23% higher than the targeted value (6 min*mg/mL), but its mean half-life and clearance were consistent with those reported in the absence of Paclitaxelum Accord.
Pharmacokinetic Interactions between Paclitaxelum Accord and Gemcitabine
Pharmacokinetic interactions between Paclitaxelum Accord and gemcitabine have not been studied in humans.
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Information checked by Dr. Sachin Kumar, MD Pharmacology
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