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

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)393-400
Number of pages8
JournalCancer chemotherapy and pharmacology
Volume67
Issue number2
DOIs
StatePublished - Feb 2011

Bibliographical note

Funding Information:
Acknowledgments Supported by: U01CA062491 “Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis” NCI; CTEP Translational Research Initiative Funding 24XS090, and 1ULRR0 25011 Clinical and Translational Science Award of the National Center for Research Resources, NIH and the American College of Clinical Pharmacy.

Keywords

  • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
  • Phase 1
  • Population pharmacokinetics
  • Triapine

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