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.