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Actions of Paclitaxel Ebewe in details
Paclitaxel Ebewe is an anticancer agent from the taxane class of drugs.
Pharmacology: Paclitaxel Ebewe 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, Paclitaxel Ebewe 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 Paclitaxel Ebewe is administered intravenously, its plasma concentration declines biphasically. The first phase shows rapid decline representing distribution of Paclitaxel Ebewe to the peripheral compartment and elimination. This initial phase is followed by a relatively slow elimination of Paclitaxel Ebewe 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 Paclitaxel Ebewe: 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 Paclitaxel Ebewe 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 Paclitaxel Ebewe: Mean terminal half-life: 9.9 hours; mean total body clearance: 12.4 L/h/m2.
The serum protein-binding of Paclitaxel Ebewe is 89%.
The liver is thought to be the primary site of metabolism for Paclitaxel Ebewe. The mean cumulative urinary recovery of unchanged Paclitaxel Ebewe has been reported as 1.8 to 12.6% of the dose.
How should I take Paclitaxel Ebewe?
Paclitaxel Ebewe is given as an injection through a needle placed into a vein. You will receive this injection in a clinic or hospital setting. Paclitaxel Ebewe must be given slowly through an IV infusion, and can take up to 24 hours to complete.
Paclitaxel Ebewe is usually given every 3 weeks. Follow your doctor's instructions.
Before your injection, you may be given other medications to help prevent a serious allergic reaction to Paclitaxel Ebewe.
Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when the Paclitaxel Ebewe is injected.
If any of Paclitaxel Ebewe gets on your skin, wash the area with soap and warm water right away.
Your breathing, blood pressure, oxygen levels, and other vital signs will be watched closely while you are receiving Paclitaxel Ebewe.
Your heart rate may also be monitored through electrocardiograph or ECG (sometimes called an EKG). This machine measures electrical activity of the heart.
Paclitaxel Ebewe can lower blood cells that help your body fight infections. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. To be sure your blood cells do not get too low, your blood will need to be tested on a regular basis. Do not miss any scheduled appointments.
Paclitaxel Ebewe administration
Paclitaxel Ebewe is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. Paclitaxel Ebewe must be given slowly, and the IV infusion can take up to 24 hours to complete.
Paclitaxel Ebewe is usually given once every 3 weeks. Follow your doctor's dosing instructions very carefully.
You may be given other medications to prevent an allergic reaction while you are receiving Paclitaxel Ebewe.
Your breathing, blood pressure, oxygen levels, kidney function, and other vital signs will be watched closely while you are receiving Paclitaxel Ebewe.
Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when Paclitaxel Ebewe is injected.
Paclitaxel Ebewe 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. Visit your doctor regularly.
Paclitaxel Ebewe pharmacology
Mechanism of Action
Paclitaxel Ebewe 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. Paclitaxel Ebewe induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
The pharmacokinetics of total Paclitaxel Ebewe following 30 and 180-minute infusions of Paclitaxel Ebewe at dose levels of 80 to 375 mg/m2 were determined in clinical studies. Dose levels of mg/m2 refer to mg of Paclitaxel Ebewe in Paclitaxel Ebewe. Following intravenous administration of Paclitaxel Ebewe, Paclitaxel Ebewe 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 Paclitaxel Ebewe for Paclitaxel Ebewe were independent of the duration of intravenous administration.
The pharmacokinetic data of 260 mg/m2 Paclitaxel Ebewe administered over a 30-minute infusion was compared to the pharmacokinetics of 175 mg/m2 Paclitaxel Ebewe injection over a 3-hour infusion. Clearance was larger (43%) and the volume of distribution was higher (53%) for Paclitaxel Ebewe than for Paclitaxel Ebewe injection. There were no differences in terminal half-lives.
Following Paclitaxel Ebewe administration to patients with solid tumors, Paclitaxel Ebewe 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 Ebewe in plasma was significantly higher with Paclitaxel Ebewe (6.2%) than with solvent-based Paclitaxel Ebewe (2.3%). This contributes to significantly higher exposure to unbound Paclitaxel Ebewe with Paclitaxel Ebewe compared with solvent-based Paclitaxel Ebewe, when the total exposure is comparable. In vitro studies of binding to human serum proteins, using Paclitaxel Ebewe 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 Paclitaxel Ebewe. The total volume of distribution is approximately 1741 L; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of Paclitaxel Ebewe.
In vitro studies with human liver microsomes and tissue slices showed that Paclitaxel Ebewe 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 Ebewe 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 Ebewe may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4.
At the clinical dose range of 80 to 300 mg/m2, the mean total clearance of Paclitaxel Ebewe 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 Paclitaxel Ebewe, 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.
Pharmacokinetics in Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of Paclitaxel Ebewe following Paclitaxel Ebewe 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 Paclitaxel Ebewe. 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 Paclitaxel Ebewe and approximately 20% increase in mean Paclitaxel Ebewe AUC compared with patients with normal hepatic function (total bilirubin ≤ULN, AST ≤ULN, n=130)..
Elimination of Paclitaxel Ebewe 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 Paclitaxel Ebewe 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 Paclitaxel Ebewe following Paclitaxel Ebewe 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 Paclitaxel Ebewe.
Other Intrinsic Factors
Population pharmacokinetic analyses for Paclitaxel Ebewe 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 Paclitaxel Ebewe.
Pharmacokinetic Interactions between Paclitaxel Ebewe and Carboplatin
Administration of carboplatin immediately after the completion of the Paclitaxel Ebewe infusion to patients with NSCLC did not cause clinically meaningful changes in Paclitaxel Ebewe 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 Paclitaxel Ebewe.
Pharmacokinetic Interactions between Paclitaxel Ebewe and Gemcitabine
Pharmacokinetic interactions between Paclitaxel Ebewe and gemcitabine have not been studied in humans.
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- NCIt. "Paclitaxel: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Paclitaxel: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology