Paclitaxel pharmacodynamics: application of a mechanism-based neutropenia model

• Published in: Biopharmaceutics & drug disposition 2001-09, Vol.22 (6), p.251-261
• Main Authors: Fetterly, Gerald J., Tamburlin, Judith M., Straubinger, Robert M.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - toxicity; Area Under Curve; Biological and medical sciences; Blood Cell Count; bone marrow; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; cancer; Chemotherapy; Erythroid Precursor Cells - drug effects; Liposomes; Male; Medical sciences; neutropenia; Neutropenia - chemically induced; Neutropenia - metabolism; Neutrophils - drug effects; Paclitaxel - administration & dosage; Paclitaxel - pharmacokinetics; Paclitaxel - toxicity; pharmacodynamics; pharmacokinetics; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.283

Antineoplastic agents exert adverse effects that impact both dose and scheduling of drug administration. Our objective was to develop a quantitative relationship between paclitaxel (taxol) exposure and pharmacodynamic endpoints, such as neutropenia or body weight loss. Paclitaxel in liposomes or Cremophor EL was administered to rats at doses of 20 or 40 mg/kg. Body weight and absolute neutrophil count were determined daily. The decrease in body weight was greater for paclitaxel in Cremophor EL than for liposomal paclitaxel, but hematological toxicity was similar. The hematological data was fit using a pharmacodynamic model to investigate the temporal delay between drug exposure and neutropenia. From the model, the lifespan of neutrophils (TN), of surviving precursor cells in bone marrow (TP), and a killing rate constant (K) were determined. The values of TN, TP, and K for liposomal paclitaxel were 95 h, 82 h, and 0.735 (μM h)−1, respectively, and for paclitaxel in Cremophor EL, 86 h, 78 h, and 0.475 (μM h)−1, respectively. Simulations of various doses indicated a dependency of the neutropenia time course on paclitaxel exposure. The entire time course of changes in neutrophil count is more informative than a single measurement if myelosuppression is prolonged and at a level associated with increased incidence of clinical adverse effects. Copyright © 2001 John Wiley & Sons, Ltd.