title: Meta-analysis of nanoparticulate paclitaxel delivery system pharmacokinetics and model prediction of associated neutropenia.
abstract: OBJECTIVE
  Nanoparticulate paclitaxel carriers have entered clinical evaluation as alternatives to the Cremophor-based standard Taxol(®) (Cre-pac). Their pharmacokinetics (PK) is complex, and factors influencing their pharmacodynamics (PD) are poorly understood. We aimed to develop a unified quantitative model for 4 paclitaxel carriers that captures systems-level PK, predicts micro-scale PK processes, and permits correlations between carrier properties and observed PD.
  
  
  METHODS
  Data consisting of 54 PK profiles and 574 observations were extracted from 20 clinical studies investigating Cre-pac, albumin-(A-pac), liposome-(L-pac), and tocopherol-(T-pac) nanocarriers. A population-PK approach was used for data analysis. All datasets were simultaneously fitted to produce a unified model. Model-based simulations explored relationships between predicted PK and myelosuppression for each formulation.
  
  
  RESULTS
  The final model employed nonlinear drug-binding mechanisms to describe Cre-pac and a delayed-release model for A-pac, L-pac, and T-pac. Estimated drug-release rate constants (h(-1)): Cre-pac (5.19), L-pac (1.26), A-pac (0.72), T-pac (0.74). Simulations of equivalent dosing schemes ranked neutropenia severity (highest to lowest): T-pac~Cre-pac>L-pac~A-pac and predicted remarkably well the clinically-observed relationships between neutropenia and free drug exposure relative to a threshold concentration.
  
  
  CONCLUSIONS
  Paclitaxel disposition was well-described for all formulations. The derived model predicts toxicodynamics of diverse paclitaxel carriers.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo State University of New York, Buffalo, New York, USA. sihema@buffalo.edu
authors.forename: Sihem
authors.initials: S
authors.lastname: Ait-Oudhia
authors.forename: Robert M
authors.initials: RM
authors.lastname: Straubinger
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
mesh_terms: D000418:Albumins / Q000008:administration & dosage / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry; D053758:Nanoparticles / Q000008:administration & dosage*; D009503:Neutropenia / Q000139:chemically induced* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D024505:Tocopherols / Q000737:chemistry
chemical_list: D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008081:Liposomes; C022131:cremophor; D011092:Polyethylene Glycols; D017239:Paclitaxel; D024505:Tocopherols