Pharmacokinetics and pharmacodynamics of nab-paclitaxel in patients with solid tumors: disposition kinetics and pharmacology distinct from solvent-based paclitaxel.
The aim of this study was to characterize population pharmacokinetics and the exposure-neutropenia relationship with nanoparticle albumin-bound (nab)-paclitaxel in patients with solid tumors. Plasma and blood concentrations of paclitaxel and neutrophil data were collected from 150 patients with various solid tumors over the nab-paclitaxel dose range of 80-375 mg/m(2). Data were analyzed using nonlinear mixed-effect modeling or logistic regression. Pharmacokinetics of nab-paclitaxel were described by a 3-compartment model with saturable distribution and elimination. The rapid disappearance of circulating paclitaxel was driven by its fast distribution to peripheral compartments; maximum rate for saturable distribution (325000 μg/h) was 40-fold greater than that for saturable elimination (8070 μg/h). Albumin was a significant covariate of paclitaxel elimination (P < .001), while total bilirubin, creatinine clearance, body size, age, sex, and tumor type had no significant or clinically relevant effect. The probability of experiencing a ≥ 50% reduction in neutrophils was best correlated to the duration above the drug concentration of 720 ng/mL. At a given exposure level, neutropenia development was positively correlated with increasing age but not significantly influenced by hepatic function, tumor type, sex, or dosing schedule. Covariate analyses supports exposure-matched dose adjustments in patients with moderate to severe hepatic impairment.
Celgene Corporation, Summit, NJ, USA.
Nianhang
N
Chen
Yan
Y
Li
Ying
Y
Ye
Maria
M
Palmisano
Rajesh
R
Chopra
Simon
S
Zhou
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000503:physiopathology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced / Q000453:epidemiology; D017711:Nonlinear Dynamics; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel
covariates; nab-paclitaxel; neutropenia; pharmacodynamics; pharmacokinetics