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

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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.

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Acknowledgments

Supported by: U01CA062491 “Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis” NCI; CTEP Translational Research Initiative Funding 24XS090, and 1ULRR025011 Clinical and Translational Science Award of the National Center for Research Resources, NIH and the American College of Clinical Pharmacy.

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Authors and Affiliations

  1. Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, 600 Highland Avenue, K4/554, Madison, WI, 53792, USA

    Jill Kolesar, Marcia Pomplun, Dona Alberti, Kyle Holen, Anne Traynor & George Wilding

  2. School of Pharmacy, University of Wisconsin, Madison, WI, USA

    Jill Kolesar

  3. Experimental and Clinical Pharmacology and Center for Forecasting Drug Response, University of Minnesota, Minneapolis, MN, USA

    Richard C. Brundage

  4. Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA

    Dona Alberti, Kyle Holen, Anne Traynor & George Wilding

  5. Cancer Therapy and Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    Percy Ivy

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  1. Jill Kolesar
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  2. Richard C. Brundage
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  3. Marcia Pomplun
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  4. Dona Alberti
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  5. Kyle Holen
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  6. Anne Traynor
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  7. Percy Ivy
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  8. George Wilding
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Correspondence to Jill Kolesar.

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Kolesar, J., Brundage, R.C., Pomplun, M. et al. Population pharmacokinetics of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine®) in cancer patients. Cancer Chemother Pharmacol 67, 393–400 (2011). https://doi.org/10.1007/s00280-010-1331-z

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  • DOI: https://doi.org/10.1007/s00280-010-1331-z

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