Chemical formula: C₄₇H₅₁NO₁₄ Molecular mass: 853.906 g/mol PubChem compound: 36314
Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation. This stability results in the inhibition of the normal dynamic reorganisation 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.
Paclitaxel contains human serum albumin-paclitaxel nanoparticles of approximately 130 nm in size, where the paclitaxel is present in a non-crystalline, amorphous state. Upon intravenous administration, the nanoparticles dissociate rapidly into soluble, albumin bound paclitaxel complexes of approximately 10 nm in size. Albumin is known to mediate endothelial caveolar transcytosis of plasma constituents, and in vitro studies demonstrated that the presence of albumin in paclitaxel enhances transport of paclitaxel across endothelial cells. It is hypothesised that this enhanced transendothelial caveolar transport is mediated by the gp-60 albumin receptor, and that there is enhanced accumulation of paclitaxel in the area of tumour due to the albumin-binding protein Secreted Protein Acidic Rich in Cysteine (SPARC).
The pharmacokinetics of total paclitaxel following 30- and 180-minute infusions of paclitaxel at dose levels of 80 to 375 mg/m 2 were determined in clinical studies. The paclitaxel exposure (AUC) increased linearly from 2653 to 16736 ng.hr/ml following dosing from 80 to 300 mg/m².
In a study in patients with advanced solid tumours, the pharmacokinetic characteristics of paclitaxel following paclitaxel administered intravenously at 260 mg/m² over 30 minutes were compared with those following 175 mg/m² of the solvent-based paclitaxel injection administered over 3 hours. Based on non-compartmental PK analysis, the plasma clearance of paclitaxel with paclitaxel was larger (43%) than that following a solvent-based paclitaxel injection and its volume of distribution was also higher (53%). There were no differences in terminal half-lives.
In a repeat dose study with 12 patients receiving paclitaxel administered intravenously at 260 mg/m², intra-patient variability in AUC was 19% (range = 3.21%-37.70%). There was no evidence for accumulation of paclitaxel with multiple treatment courses.
Following paclitaxel administration to patients with solid tumours, paclitaxel is evenly distributed into blood cells and plasma and is highly bound to plasma proteins (94%).
The protein binding of paclitaxel following paclitaxel was evaluated by ultrafiltration in a within-patient comparison study. The fraction of free paclitaxel was significantly higher with paclitaxel (6.2%) than with solvent-based paclitaxel (2.3%). This resulted in significantly higher exposure to unbound paclitaxel with paclitaxel compared with solvent-based paclitaxel, even though the total exposure is comparable. This is possibly due to paclitaxel not being trapped in Cremophor EL micelles as with solvent-based paclitaxel. Based on the published literature, in vitro studies of binding to human serum proteins, (using paclitaxel at 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.
Based on population pharmacokinetic analysis, the total volume of distribution is approximately 1741 L; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel.
Based on the published literature, in vitro studies with human liver microsomes and tissue slices show that paclitaxel is metabolised primarily to 6α-hydroxypaclitaxel; and to two minor metabolites, 3'-phydroxypaclitaxel and 6α-3'p-dihydroxypaclitaxel. The formation of these hydroxylated metabolites is catalysed by CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4 isoenzymes, respectively.
In patients with metastatic breast cancer, after a 30-minute infusion of paclitaxel at 260 mg/m², the mean value for cumulative urinary excretion of unchanged active substance accounted for 4% of the total administered dose with less than 1% as the metabolites 6α-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel, indicating extensive non-renal clearance. Paclitaxel is principally eliminated by hepatic metabolism and biliary excretion.
At the clinical dose range of 80 to 300 mg/m², the mean plasma clearance of paclitaxel ranges from 13 to 30 L/h/m², and the mean terminal half-life ranges from 13 to 27 hours.
The effect of hepatic impairment on population pharmacokinetics of paclitaxel was studied in patients with advanced solid tumours. This analysis included patients with normal hepatic function (n=130), and pre-existing mild (n=8), moderate (n=7), or severe (n=5) hepatic impairment (according to NCI Organ Dysfunction Working Group criteria). The results show that mild hepatic impairment (total bilirubin >1 to ≤1.5 x ULN) has no clinically important effect on pharmacokinetics of paclitaxel. Patients with moderate (total bilirubin >1.5 to ≤3 x ULN) or severe (total bilirubin >3 to ≤5 x ULN) hepatic impairment have a 22% to 26% decrease in the maximum elimination rate of paclitaxel and approximately 20% increase in mean paclitaxel AUC compared with patients with normal hepatic function. Hepatic impairment has no effect on mean paclitaxel Cmax. In addition, elimination of paclitaxel 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 exposure.
Pharmacokinetic data are not available for patients with total bilirubin >5 x ULN or for patients with metastatic adenocarcinoma of the pancreas.
Population pharmacokinetic analysis included patients with normal renal function (n=65), and pre-existing mild (n=61), moderate (n=23), or severe (n=l) renal impairment (according to draft FDA guidance criteria 2010). Mild to moderate renal impairment (creatinine clearance ≥30 to <90 ml/min) has no clinically important effect on the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel. Pharmacokinetic data are insufficient for patients with severe renal impairment and not available for patients with end stage kidney disease.
Population pharmacokinetic analysis for paclitaxel included patients with ages ranging from 24 to 85 years old and shows that age does not significantly influence the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel.
Pharmacokinetic/pharmacodynamic modelling using data from 125 patients with advanced solid tumours indicates that patients ≥65 years of age may be more susceptible to development of neutropenia within the first treatment cycle, although the plasma paclitaxel exposure is not affected by age.
The pharmacokinetics of paclitaxel following 30 minutes of intravenous administration at dose levels of 120 mg/m² to 270 mg/m² were determined in 64 patients (2 to ≤18 years) in Phase 1 of a Phase ½ study in recurrent or refractory paediatric solid tumours. Following dosing increase from 120 to 270 mg/m², the paclitaxel mean AUC(0-inf) and Cmax ranged from 8867 to 14361 ng*hr/ml and from 3488 to 8078 ng/ml, respectively.
Dose normalized peak drug exposure values were comparable across the dose range studied; however, dose-normalized total drug exposure values were only comparable across 120 mg/m² to 240 mg/m²; with lower dose-normalized AUC∞ at the 270 mg/m² dose level. At the MTD of 240 mg/m², the mean CL was 19.1 L/h and the mean terminal half-life was 13.5 hours.
In children and adolescent patients, exposure to paclitaxel increased with higher dosing and weekly drug exposures were higher than in adult patients.
Population pharmacokinetic analyses for paclitaxel indicate that gender, race (Asian vs. White), and type of solid tumours do not have a clinically important effect on systemic exposure (AUC and Cmax) of paclitaxel. Patients weighing 50 kg had paclitaxel AUC approximately 25% lower than those weighing 75 kg. The clinical relevance of this finding is uncertain.
The carcinogenic potential of paclitaxel has not been studied. However, based on the published literature, paclitaxel is a potentially carcinogenic and genotoxic agent at clinical doses, based upon its pharmacodynamic mechanism of action. Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel has been shown to be genotoxic in vivo (micronucleus test in mice), but it did not induce mutagenicity in the Ames test or the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl transferase (CHO/HGPRT) gene mutation assay.
Paclitaxel at doses below the human therapeutic dose was associated with low fertility when administered prior and during mating in male and female rats and foetal toxicity in rats. Animal studies with paclitaxel showed non-reversible, toxic effects on the male reproductive organs at clinically relevant exposure levels.
Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Following intravenous administration of radiolabelled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations.
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