ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension)(十九)
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Pharmacokinetics in Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of paclitaxel following ABRAXANE 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. 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 and approximately 20% increase in mean paclitaxel AUC compared with patients with normal hepatic function (total bilirubin ≤ULN, AST ≤ULN, n=130). [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].
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 ABRAXANE exposure. Pharmacokinetic data are not available for patients with total bilirubin >5 x ULN or for patients with metastatic adenocarcinoma of the pancreas [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].
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 following ABRAXANE 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 [see Use in Specific Populations (8.7)].
Other Intrinsic Factors
Population pharmacokinetic analyses for ABRAXANE 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.
Pharmacokinetic Interactions between ABRAXANE and Carboplatin
Administration of carboplatin immediately after the completion of the ABRAXANE infusion to patients with NSCLC did not cause clinically meaningful changes in paclitaxel 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.
Pharmacokinetic Interactions between ABRAXANE and Gemcitabine
Pharmacokinetic interactions between ABRAXANE and gemcitabine have not been studied in humans.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of ABRAXANE has not been studied.
Paclitaxel was clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). ABRAXANE was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.
Administration of paclitaxel formulated as albumin-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a body surfac |
