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


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.
Ng
Chee M
CM
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA. ngc1@email.chop.edu
Patnaik
A
A
Beeram
M
M
Lin
C C
CC
Takimoto
C H
CH
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004148:Dioxolanes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced*; D055815:Young Adult
D000970:Antineoplastic Agents; D004148:Dioxolanes; C074908:troxacitabine; D003596:Cytosine; D002945:Cisplatin