Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 2, pp 393–400

Population pharmacokinetics of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine®) in cancer patients

  • Jill Kolesar
  • Richard C. Brundage
  • Marcia Pomplun
  • Dona Alberti
  • Kyle Holen
  • Anne Traynor
  • Percy Ivy
  • George Wilding
Original Article

DOI: 10.1007/s00280-010-1331-z

Cite this article as:
Kolesar, J., Brundage, R.C., Pomplun, M. et al. Cancer Chemother Pharmacol (2011) 67: 393. doi:10.1007/s00280-010-1331-z

Abstract

Purpose

The purpose of this study was to develop a population pharmacokinetic (PK) model for 3-AP, to evaluate the effect of ABCB1 polymorphisms on the pharmacokinetic profile of 3-AP, and to assess the relationship between 3AP disposition and patient covariates.

Methods

A total of 40 patients with advanced cancer from two phase 1 studies were included in the population PK model building. Patients received 3-AP 25–105 mg/m2 IV on day 1. 3-AP plasma and erythrocyte levels were sampled at 10 timepoints over a 24-h period and measured by a validated HPLC method. Data were analyzed by a nonlinear mixed-effects modeling approach using the NONMEM system.

Results

3-AP pharmacokinetics were described as a 3-compartment model with first-order elimination, with one compartment representing the plasma and another representing erythrocyte concentrations. Gender was associated with volume of distribution, in which women had a lower V2. The number of cycles administered was associated with clearance; those with decreased clearance were more likely to receive less than 2 cycles before going off study.

Conclusion

This study suggests that monitoring 3-AP plasma concentrations in the first cycle and dose adjustment in those with decreased clearance may be helpful in decreasing toxicity associated with the 3-AP.

Keywords

Triapine® 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone Population pharmacokinetics Phase 1 

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Jill Kolesar
    • 1
    • 2
  • Richard C. Brundage
    • 3
  • Marcia Pomplun
    • 1
  • Dona Alberti
    • 1
    • 4
  • Kyle Holen
    • 1
    • 4
  • Anne Traynor
    • 1
    • 4
  • Percy Ivy
    • 5
  • George Wilding
    • 1
    • 4
  1. 1.Paul P. Carbone Comprehensive Cancer CenterUniversity of WisconsinMadisonUSA
  2. 2.School of PharmacyUniversity of WisconsinMadisonUSA
  3. 3.Experimental and Clinical Pharmacology and Center for Forecasting Drug ResponseUniversity of MinnesotaMinneapolisUSA
  4. 4.Department of Medicine, School of Medicine and Public HealthUniversity of WisconsinMadisonUSA
  5. 5.Cancer Therapy and Evaluation ProgramNational Cancer InstituteBethesdaUSA

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