Mechanism-based pharmacokinetic/pharmacodynamic model for troxacitabine-induced neutropenia in cancer patients

• Published in: Cancer chemotherapy and pharmacology 2011-05, Vol.67 (5), p.985-994
• Main Authors: Ng, Chee M., Patnaik, A., Beeram, M., Lin, C. C., Takimoto, C. H.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Cancer Research; Cisplatin - administration & dosage; Cytosine - administration & dosage; Cytosine - analogs & derivatives; Cytosine - pharmacokinetics; Cytosine - pharmacology; Dioxolanes - administration & dosage; Dioxolanes - pharmacokinetics; Dioxolanes - pharmacology; Female; Hematologic and hematopoietic diseases; Humans; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Monte Carlo Method; Neoplasms - drug therapy; Neutropenia - chemically induced; Oncology; Original Article; Other diseases. Hematologic involvement in other diseases; Pharmacology. Drug treatments; Pharmacology/Toxicology; Young Adult
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-010-1393-y

Purposes The objective of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PK/PD) model in describing troxacitabine-induced neutropenia in patients with cancer. Methods A total of 727 PK/PD samples from 31 patients with cancer were included in the analysis. A mechanism-based population PD model was developed to describe neutropenia and the final model consisted of (1) a drug-sensitive uncommitted progenitor cell compartment (2) three transit compartments, and (3) a circulating neutrophil compartment with feedback mechanism. The troxacitabine affected the proliferation of sensitive progenitor cells through an inhibitory E max model. The model parameters were estimated using the MCPEM algorithm that was implemented in a parallel computing platform consisting of a single computer equipped with a quad-core INTEL central processor unit. Results and conclusions The mechanism-based PK/PD model developed using parallelized MCPEM method adequately describes the complex relationship between the exposure and absolute neutrophil counts in troxacitabine-treated patients with cancer. The simulation results suggested that the less frequent dosing schedule of troxacitabine used currently in clinical studies was associated with less incidence of neutropenia compared to more frequent dosing schedule.