Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 5, pp 1145–1155

A combined pharmacokinetic model for the hypoxia-targeted prodrug PR-104A in humans, dogs, rats and mice predicts species differences in clearance and toxicity

  • Kashyap Patel
  • Steve S. F. Choy
  • Kevin O. Hicks
  • Teresa J. Melink
  • Nicholas H. G. Holford
  • William R. Wilson
Original Article

Abstract

Background

PR-104 is a phosphate ester that is systemically converted to the corresponding alcohol PR-104A. The latter is activated by nitroreduction in tumours to cytotoxic DNA cross-linking metabolites. Here, we report a population pharmacokinetic (PK) model for PR-104 and PR-104A in non-human species and in humans.

Methods

A compartmental model was used to fit plasma PR-104 and PR-104A concentration–time data after intravenous (i.v.) dosing of humans, Beagle dogs, Sprague–Dawley rats and CD-1 nude mice. Intraperitoneal (i.p.) PR-104 and i.v. PR-104A dosing of mice was also investigated. Protein binding was measured in plasma from each species. Unbound drug clearances and volumes were scaled allometrically.

Results

A two-compartment model described the disposition of PR-104 and PR-104A in all four species. PR-104 was cleared rapidly by first-order (mice, rats, dogs) or mixed-order (humans) metabolism to PR-104A in the central compartment. The estimated unbound human clearance of PR104A was 211 L/h/70 kg, with a steady state unbound volume of 105 L/70 kg. The size equivalent unbound PR-104A clearance was 2.5 times faster in dogs, 0.78 times slower in rats and 0.63 times slower in mice, which may reflect reported species differences in PR-104A O-glucuronidation.

Conclusions

The PK model demonstrates faster size equivalent clearance of PR-104A in dogs and humans than rodents. Dose-limiting myelotoxicity restricts the exposure of PR-104A in humans to approximately 25% of that achievable in mice.

Keywords

Hypoxia-activated prodrugs Nitrogen mustards Pharmacokinetics PR-104 Allometry 

Supplementary material

280_2010_1412_MOESM1_ESM.doc (148 kb)
Supplementary material 1 (DOC 133 kb)

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Kashyap Patel
    • 1
  • Steve S. F. Choy
    • 2
  • Kevin O. Hicks
    • 1
  • Teresa J. Melink
    • 3
  • Nicholas H. G. Holford
    • 2
  • William R. Wilson
    • 1
  1. 1.Faculty of Medical and Health SciencesAuckland Cancer Society Research Centre, The University of AucklandAucklandNew Zealand
  2. 2.Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health SciencesThe University of AucklandAucklandNew Zealand
  3. 3.Proacta Inc. 9255 Towne Centre DriveSan DiegoUSA

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